Conditions - Cancer

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Green Tea Consumption and Prostate Cancer Risk in Japanese Men: A Prospective Study.

Authors: Kurahashi N, Sasazuki S, Iwasaki M, Inoue M; Shoichiro Tsugane for the JPHC Study Group. Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.

Source: Am J Epidemiol. 2007 Sep 29;

The incidence of prostate cancer is much lower in Asian than Western populations. Given that environmental factors such as dietary habits may play a major role in the causation of prostate cancer and the high consumption of green tea in Asian populations, this low incidence may be partly due to the effects of green tea. The JPHC Study (Japan Public Health Center-based Prospective Study) was established in 1990 for cohort I and in 1993 for cohort II. The subjects were 49,920 men aged 40-69 years who completed a questionnaire that included their green tea consumption habit at baseline and were followed until the end of 2004. During this time, 404 men were newly diagnosed with prostate cancer, of whom 114 had advanced cases, 271 were localized, and 19 were of an undetermined stage. Green tea was not associated with localized prostate cancer. However, consumption was associated with a dose-dependent decrease in the risk of advanced prostate cancer. The multivariate relative risk was 0.52 (95% confidence interval: 0.28, 0.96) for men drinking 5 or more cups/day compared with less than 1 cup/day (p(trend) = 0.01). Green tea may be associated with a decreased risk of advanced prostate cancer.

Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study.

Authors: Osterlund P, Ruotsalainen T, Korpela R, Saxelin M, Ollus A, Valta P, Kouri M, Elomaa I, Joensuu H. 1Department of Oncology, Helsinki University Central Hospital, PO Box 180, 00029 HUS Helsinki, Finland.

Source: Br J Cancer. 2007 Oct 22;97(8):1028-34. Epub 2007 Sep 25.

5-Fluorouracil (5-FU)-based chemotherapy is frequently associated with diarrhoea. We compared two 5-FU-based regimens and the effect of Lactobacillus and fibre supplementation on treatment tolerability. Patients diagnosed with colorectal cancer (n=150) were randomly allocated to receive monthly 5-FU and leucovorin bolus injections (the Mayo regimen) or a bimonthly 5-FU bolus plus continuous infusion (the simplified de Gramont regimen) for 24 weeks as postoperative adjuvant therapy. On the basis of random allocation, the study participants did or did not receive Lactobacillus rhamnosus GG supplementation (1-2 x 10(10) per day) and fibre (11 g guar gum per day) during chemotherapy. Patients who received Lactobacillus had less grade 3 or 4 diarrhoea (22 vs 37%, P=0.027), reported less abdominal discomfort, needed less hospital care and had fewer chemotherapy dose reductions due to bowel toxicity. No Lactobacillus-related toxicity was detected. Guar gum supplementation had no influence on chemotherapy tolerability. The simplified de Gramont regimen was associated with fewer grade 3 or 4 adverse effects than the Mayo regimen (45 vs 89%), and with less diarrhoea. We conclude that Lactobacillus GG supplementation is well tolerated and may reduce the frequency of severe diarrhoea and abdominal discomfort related to 5-FU-based chemotherapy.British Journal of Cancer (2007) 97, 1028-1034. doi:10.1038/sj.bjc.6603990 www.bjcancer.com Published online 25 September 2007.

Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort.

Authors: Peters U, Littman AJ, Kristal AR, Patterson RE, Potter JD, White E. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North M4-B402, P.O. Box 19024, Seattle, WA, 98109-1024, USA.

Source: Cancer Causes Control. 2007 Oct 18;

OBJECTIVE: Vitamin E and selenium are promising nutrients for the prevention of prostate cancer, and both are currently being tested in a large randomized trial for prostate cancer. However, results are not expected for at least 6 years. We aimed to investigate the association of vitamin E and selenium supplementation with prostate cancer in the VITamins And Lifestyle (VITAL) study, a cohort study specifically designed to examine supplement use and future cancer risk.

METHODS: In a prospective design, 35,242 men recruited between 2000 and 2002 from western Washington State completed a questionnaire, including detailed questions about vitamin E and selenium supplement intake during the past 10 years from brand-specific multivitamins and single supplements. Using linkage to the western Washington SEER cancer registry, we documented 830 new cases of prostate cancer from baseline through December 2004.

RESULTS: A 10-year average intake of supplemental vitamin E was not associated with a reduced prostate cancer risk overall [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.65-1.1 for >/=400 IU/day vs. non-use, p for trend 0.36]; however, risk for advanced prostate cancer (regionally invasive or distant metastatic, n = 123) decreased significantly with greater intake of supplemental vitamin E (HR 0.43, 95% CI 0.19-1.0 for 10-year average intake >/=400 IU/day vs. non-use, p for trend 0.03). There was no association between selenium supplementation and prostate cancer risk (HR 0.90, 95% CI 0.62-1.3 for 10-year average intake >50 mug/day vs. non-use, p for trend 0.97).

CONCLUSIONS: In this prospective cohort, long-term supplemental intake of vitamin E and selenium were not associated with prostate cancer risk overall; however, risk of clinically relevant advanced disease was reduced with greater long-term vitamin E supplementation.

Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration.

Authors: Yeom CH, Jung GC, Song KJ. Department of Family Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea.

Source: J Korean Med Sci. 2007 Feb;22(1):7-11.

Over the years there has been a great deal of controversy on the effect of vitamin C on cancer. To investigate the effects of vitamin C on cancer patients' health-related quality of life, we prospectively studied 39 terminal cancer patients. All patients were given an intravenous administration of 10 g vitamin C twice with a 3-day interval and an oral intake of 4 g vitamin C daily for a week. And then we investigated demographic data and assessed changes in patients' quality of life after administration of vitamin C. Quality of life was assessed with EORTC QLQ-C30. In the global health/quality of life scale, health score improved from 36+/-18 to 55+/-16 after administration of vitamin C (p=0.001). In functional scale, the patients reported significantly higher scores for physical, role, emotional, and cognitive function after administration of vitamin C (p<0.05). In symptom scale, the patients reported significantly lower scores for fatigue, nausea/vomiting, pain, and appetite loss after administration of vitamin C (p<0.005). The other function and symptom scales were not significantly changed after administration of vitamin C. In terminal cancer patients, the quality of life is as important as cure. Although there is still controversy regarding anticancer effects of vitamin C, the use of vitamin C is considered a safe and effective therapy to improve the quality of life of terminal cancer patients.

Effect of acupressure on nausea and vomiting induced by chemotherapy in cancer patients.

Authors: Gardani G, Cerrone R, Biella C, Mancini L, Proserpio E, Casiraghi M, Travisi O,Meregalli M, Trabattoni P, Colombo L, Giani L, Vaghi M, Lissoni P.

Source: Minerva Med. 2006 Oct;97(5):391-4.

AIM: Corticosteroids, antidopaminergig agents and 5-HT3 antagonists are the most commonly used drugs in the treatment of chemotherapy-induced vomiting. Acupuncture and acupressure have also appeared to exert antiemetic effects. The aim of this study was to evaluate the efficacy of acupressure in the treatment of chemotherapy-induced vomiting resistant to the standard antiemetic therapies.

METHODS: The study included 40 consecutive advanced cancer patients with untreatable chemotherapy-induced vomiting. Colorectal cancer, lung cancer and breast cancer were the neoplasm most frequent in our patients. According to tumour histotype, patients received chemotherapeutic regimens containing the main emetic cytotoxic agents, including cisplatin and athracyclines. Acupressure was made by PC6 point stimulation for at least 6 h/day at the onset of chemotherapy.

RESULTS: The therapeutic approach was well accepted by the overall patients. An evident improvement in the emetic symptomatology was achieved in 28/40 (70%) patients, without significant differences in relation to neither tumor histotype, nor type of chemotherapeutic agent.

CONCLUSIONS: This preliminary study seems to suggest that a bioenergetic approach by acupressure on PC6 point may be effective in the treatment of chemotherapy-induced vomiting resistant to the conventional pharmacological strategies, as previously demonstrated for vomiting occurring during pregnancy.

Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition.

Authors: Choi H, Chun YS, Kim SW, Kim MS, Park JW.

Source: Mol Pharmacol. 2006 Nov;70(5):1664-71. Epub 2006 Jul 3`

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1alpha. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.

Food, nutrient and heterocyclic amine intake and the risk of bladder cancer.

Authors: García-Closas R, García-Closas M, Kogevinas M, Malats N, Silverman D, Serra C, Tardón A, Carrato A, Castaño-Vinyals G, Dosemeci M, Moore L, Rothman N, Sinha R.

Source: Eur J Cancer. 2007 Jul;43(11):1731-40. Epub 2007 Jun 26.

Fruit and vegetable intake has been linked to bladder cancer risk; however, evidence for other foods or specific dietary factors is inconclusive. The association between diet and bladder cancer risk was evaluated among 912 incident bladder cancer cases and 873 controls in Spain. Data were consistent with a reduced bladder cancer risk associated with high fruit intake; however, the association was significant only among current smokers (OR (95% CI) for 5th versus 1st quintile: 0.5 (0.3-0.9), p trend=0.009). Evaluation of food subgroups showed significant inverse associations with high intakes of berries, Liliaceae vegetables and yellow-orange vegetables. The latter association was stronger among individuals with the GSTM1 present than the null genotype (0.4 (0.2, 0.7) and 0.9 (0.6, 1.3), respectively; p for interaction=0.04). Meat or fish intake, their cooking methods or level of doneness, or heterocyclic amine intakes were not significantly associated with risk. Intake of folate, other B-vitamins (B12, B6, B2) and retinol was also associated with a reduced risk, the strongest associations being for vitamin B6 (0.6 (0.4, 0.8) p trend=0.0006) and retinol (0.6 (0.4-0.9) p trend=0.004). Our findings indicate that fruit and vegetable intake, as well as B-vitamin and retinol intake might be associated with a reduced bladder cancer risk.

One year pre-post intervention follow-up of psychological, immune, endocrine and blood pressure outcomes of mindfulness-based stress reduction (MBSR) in breast and prostate cancer outpatients.

Authors: Carlson LE, Speca M, Patel KD, Faris P.

Source: Brain Behav Immun. 2007 May 21

OBJECTIVES: This study investigated the ongoing effects of participation in a mindfulness-based stress reduction (MBSR) program on quality of life (QL), symptoms of stress, mood and endocrine, immune and autonomic parameters in early stage breast and prostate cancer patients.

METHODS: Forty-nine patients with breast cancer and 10 with prostate cancer enrolled in an eight-week MBSR program that incorporated relaxation, meditation, gentle yoga and daily home practice. Demographic and health behaviors, QL, mood, stress symptoms, salivary cortisol levels, immune cell counts, intracellular cytokine production, blood pressure (BP) and heart rate (HR) were assessed pre- and post-intervention, and at 6- and 12-month follow-up.

RESULTS: Fifty-nine, 51, 47 and 41 patients were assessed pre- and post-intervention and at 6- and 12-month follow-up, respectively, although not all participants provided data on all outcomes at each time point. Linear mixed modeling showed significant improvements in overall symptoms of stress which were maintained over the follow-up period. Cortisol levels decreased systematically over the course of the follow-up. Immune patterns over the year supported a continued reduction in Th1 (pro-inflammatory) cytokines. Systolic blood pressure (SBP) decreased from pre- to post-intervention and HR was positively associated with self-reported symptoms of stress.

CONCLUSIONS: MBSR program participation was associated with enhanced quality of life and decreased stress symptoms, altered cortisol and immune patterns consistent with less stress and mood disturbance, and decreased blood pressure. These pilot data represent a preliminary investigation of the longer-term relationships between MBSR program participation and a range of potentially important biomarkers.

Cancer preventive properties of ginger: A brief review.

Authors: Shukla Y, Singh M.

Source: Food Chem Toxicol. 2007 May;45(5):683-90. Epub 2006 Nov 12.

Ginger, the rhizome of Zingiber officinalis, one of the most widely used species of the ginger family, is a common condiment for various foods and beverages. Ginger has a long history of medicinal use dating back 2500 years. Ginger has been traditionally used from time immemorial for varied human ailments in different parts of the globe, to aid digestion and treat stomach upset, diarrhoea, and nausea. Some pungent constituents present in ginger and other zingiberaceous plants have potent antioxidant and anti-inflammatory activities, and some of them exhibit cancer preventive activity in experimental carcinogenesis. The anticancer properties of ginger are attributed to the presence of certain pungent vallinoids, viz. [6]-gingerol and [6]-paradol, as well as some other constituents like shogaols, zingerone etc. A number of mechanisms that may be involved in the chemopreventive effects of ginger and its components have been reported from the laboratory studies in a wide range of experimental models.

Vitamin A, retinol, and carotenoids and the risk of gastric cancer: a prospective cohort study.

Authors: Larsson SC, Bergkvist L, Naslund I, Rutegard J, Wolk A.

Source: Am J Clin Nutr. 2007 Feb;85(2):497-503.

BACKGROUND: Vitamin A may influence gastric carcinogenesis through its essential role in controlling cell proliferation and differentiation. However, epidemiologic studies of vitamin A, retinol (preformed vitamin A), and provitamin A carotenoids in relation to the risk of gastric cancer have documented inconsistent results.

OBJECTIVE: The objective of the study was to examine the associations between intakes of vitamin A, retinol, and specific carotenoids and the risk of gastric cancer in a prospective population-based cohort study of Swedish adults.

DESIGN: The study cohort consisted of 82 002 Swedish adults aged 45-83 y who had completed a food-frequency questionnaire in 1997. The participants were followed through June 2005.

RESULTS: During a mean 7.2-y follow-up, 139 incident cases of gastric cancer were diagnosed. High intakes of vitamin A and retinol from foods only (dietary intake) and from foods and supplements combined (total intake) and of dietary alpha-carotene and beta-carotene were associated with a lower risk of gastric cancer. The multivariate relative risks for the highest versus lowest quartiles of intake were 0.53 (95% CI: 0.32, 0.89; P for trend = 0.02) for total vitamin A, 0.56 (95% CI: 0.33, 0.95; P for trend = 0.05) for total retinol, 0.50 (95% CI: 0.30, 0.83; P for trend = 0.03) for alpha-carotene, and 0.55 (95% CI: 0.32, 0.94; P for trend = 0.07) for beta-carotene. No significant associations were found for beta-cryptoxanthin, lutein and zeaxanthin, or lycopene intake.

CONCLUSION: High intakes of vitamin A, retinol, and provitamin A carotenoids may reduce the risk of gastric cancer.

Phellinus linteus activates different pathways to induce apoptosis in prostate cancer cells.

Authors: Zhu T, Guo J, Collins L, Kelly J, Xiao ZJ, Kim SH, Chen CY.

Source: Br J Cancer. 2007 Jan 30.

It is known that polysaccharides extracted from the Phellinus linteus (PL) mushroom possess antitumour activity. We previously have demonstrated that high doses of PL render murine or human lung cancer cells susceptible to apoptosis. However, the molecular mechanisms of PL-mediated apoptosis have not been fully explored. In this study, we demonstrate that LNCaP cells expressing the androgen receptor (AR) are highly susceptible to apoptosis in response to treatment with high doses of PL. In this process, caspase 8 and its downstream effectors (such as BID), as well as ER stress-related, apoptotic signalling, are activated. In contrast, a moderate amount of apoptosis occurs in PC3 cells (that lack AR) after the same treatment, which does not activate ER-mediated apoptotic signalling. We also show that, in the process of PL-induced apoptosis, caspase 2 is induced in LNCaP cells, but not in PC3 cells. However, LNCaP cells that express a mutated AR or LNCaP cells treated with a caspase 2 inhibitor blocked ER stress-induced apoptotic signals. The magnitudes of the induction of apoptosis in these cells are comparable with what occurred in the PC3 cells. The data demonstrate that high doses of PL activate the AR-dependent and independent apoptotic pathways. Our study also suggests that caspase 2 is a key target in the determination of the susceptibility of prostate cancer cells to PL-induced apoptosis.British Journal of Cancer advance online publication, 30 January 2007; doi:10.1038/sj.bjc.6603595 www.bjcancer.com.

Nutrition and cancer risk: an overview.

Authors: Fernandez E, Gallus S, La Vecchia C.

Source: J Br Menopause Soc. 2006 Dec;12(4):139-42.

The role of diet in cancer is a major public health issue Foods associated with a low risk of cancer are those typically included in the so-called Mediterranean diet, which is also associated with low mortality rates from cardiovascular disease. Implementing such a diet would involve increasing the consumption of fruits, vegetables, cereals, whole-grain foods and fish, while reducing the intake of refined carbohydrates and red meat. In addition, olive oil should replace saturated fats. Omega-3 fatty acids found in fish inhibit the growth in vitro of colon, breast and prostate cancers. Fibre can bind bile acids, which produce carcinogenic metabolites, and fermented fibre produces volatile fatty acids that can protect against colon cancer. It has been hypothesized that the anti-cancer actions of olive oil may relate to the ability of its mono-unsaturated fatty acid, oleic acid, to regulate oncogenes.

Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study.

Authors: Boeing H, Dietrich T, Hoffmann K, Pischon T, Ferrari P, Lahmann PH, Boutron-Ruault MC, Clavel-Chapelon F, Allen N, Key T, Skeie G, Lund E, Olsen A, Tjonneland A, Overvad K, Jensen MK, Rohrmann S, Linseisen J, Trichopoulou A, Bamia C, Psaltopoulou T, We

Source: Cancer Causes Control. 2006 Sep;17(7):957-69.Click here to read

Epidemiologic studies suggest that a high intake of fruits and vegetables is associated with decreased risk of cancers of the upper aero-digestive tract. We studied data from 345,904 subjects of the prospective European Investigation into Cancer and Nutrition (EPIC) recruited in seven European countries, who had completed a dietary questionnaire in 1992-1998. During 2,182,560 person years of observation 352 histologically verified incident squamous cell cancer (SCC) cases (255 males; 97 females) of the oral cavity, pharynx, larynx, and esophagus were identified. Linear and restricted cubic spline Cox regressions were fitted on variables of intake of fruits and vegetables and adjusted for potential confounders. We observed a significant inverse association with combined total fruits and vegetables intake (estimated relative risk (RR) = 0.91; 95% confidence interval (95% CI) 0.83-1.00 per 80 g/d of consumption), and nearly significant inverse associations in separate analyses with total fruits and total vegetables intake (RR: 0.97 (95% CI: 0.92-1.02) and RR = 0.89 (95% CI: 0.78-1.02) per 40 g/d of consumption). Overall, vegetable subgroups were not related to risk with the exception of intake of root vegetables in men. Restricted cubic spline regression did not improve the linear model fits except for total fruits and vegetables and total fruits with a significant decrease in risk at low intake levels (<120 g/d) for fruits. Dietary recommendations should consider the potential benefit of increasing fruits and vegetables consumption for reducing the risk of cancers of the upper aero-digestive tract, particularly at low intake.

A vegetable to meat consumption ratio as a relevant factor determining cancer preventive diet. The Mediterranean versus other European countries.

Authors: Kapiszewska M.

Source: Forum Nutr. 2006;59:130-53.

The observed growth of cancer incidence in certain regions has been usually linked to frequent consumption of 'unhealthy' food. Such food often contains genotoxic substances as heterocyclic aromatic amines (HAAs) and/or polycyclic aromatic hydrocarbones (PAHs), occurring during food preparation, which induce DNA damage in cells. These substances are mainly formed during frying or grilling of meat and they can be removed from the body in a two-stage metabolic process of detoxification (phase 1 and phase 2). If they are not excreted, they form DNA adducts. The effectiveness of detoxification depends on the activity of enzymes encoded by polymorphic genes. A diet containing plenty of fruits and vegetables, due to the presence of biologically active polyphenols, can modulate activity of detoxifying enzymes. Such a diet can decrease the extent of DNA adducts, breaks and oxidative damage, supporting the body's enzymatic system in sufficient removal of DNA damage. The antioxidant vitamins' content in such a diet also enhances the DNA protection by increasing the scavenging of radical oxidative species that occurs during metabolic reactions. The lack of balance between the amount of 'unhealthy' and 'healthy' food leads to the accumulation of unrepaired damage, initiating DNA instability and inducing cancer development. Such damage is often used as a biomarker of cancer risk in epidemiological studies. Moreover, in in vitro studies, the amount of the DNA damage is used as indicator of the protective ability of vitamins, plant extracts and/or individual flavonoids. The incidences of certain dietaryrelated cancers in European Mediterranean countries is lower than in Central and Northern European countries; there is simultaneously variation in the habitual diet in these regions. This suggests that some features of routine nutrition in the Mediterranean countries may be responsible for this preventing effect. However, inconsistency in the epidemiological data, associating the meat and fruit and vegetable intake with cancer risk, suggests that another strategy for evaluation dietary influence on cancer risk should be undertaken. This article argues that it is not the consumption of a single food product or an individual component of diet, but rather a proper ratio of vegetable to meat consumption that is responsible for cancer prevention. This hypothesis is tested comparing the association between certain dietaryrelated cancer incidences (colon & rectum, breast and prostate cancer), registered in 2002, with the ratio between consumption of these two groups of food products in the Mediterranean region and in Central and Northern European region over the last three decades. The results clearly showed that both the ratio between vegetables and meat consumption as well as the ratio between the amount of energy from vegetables and from animal products can be used successfully to evaluate the dietary pattern related to cancer risk.

Molecular effects of the isoflavonoid genistein in prostate cancer.

Authors: Bektic J, Guggenberger R, Eder IE, Pelzer AE, Berger AP, Bartsch G, Klocker H.

Source: Clin Prostate Cancer. 2005 Sep;4(2):124-9.

Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.

cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF-{kappa}B activation and subsequent COX-2 expression in hairless mouse skin by targeting I{kappa}B kinase and PI3K-Akt.

Authors: Hwang DM, Kundu JK, Shin JW, Lee HJ, Surh YJ.

Source: Carcinogenesis. 2006 Aug 31;

Conjugated linoleic acid (CLA) has been reported to inhibit mouse skin carcinogenesis, particularly in the promotion stage, but underlying molecular mechanisms remain poorly understood. Since persistent induction of cyclooxygenase-2 (COX-2) is frequently implicated in carcinogenesis, we investigated the effect of cis-9,trans-11-CLA (9Z,11E-CLA) on the tumor promoter-induced COX-2 expression in HR-1 hairless mouse skin in vivo. Topical application of 9Z,11E-CLA caused significant inhibition of COX-2 expression at 6 h induced by 10 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) in HR-1 mouse skin. Since NF-kappaB is known to regulate COX-2 gene expression, we determined the effect of 9Z,11E-CLA on TPA-induced NF-kappaB activation. Treatment of mouse skin with 9Z,11E-CLA reduced TPA-induced DNA binding as well as nuclear translocation of NF-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. In addition, 9Z,11E-CLA attenuated TPA-induced phosphorylation of extracellular signal regulated protein kinase, p38 mitogen-activated protein kinase and Akt. To further elucidate the molecular mechanism underlying the inactivation of NF-kappaB by 9Z,11E-CLA, we further investigated its effect on TPA-induced activation of IkappaB kinase (IKK), an upstream kinase that regulates NF-kappaB via phosphorylation and degradation of IkappaBalpha. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKKalpha/beta in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKbeta-specific inhibitor SC-514 (1 micromol) attenuated TPA-induced activation of Akt and NF-kappaB, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-kappaB driven-COX-2 expression by blocking the IKK and PI3K-Akt signaling in TPA-treated hairless mouse skin in vivo, which may account for its previously reported anti-tumor promoting effects.

Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells.

Authors: Beevers CS, Li F, Liu L, Huang S.

Source: Int J Cancer. 2006 Aug 15;119(4):757-64.

Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Here we show that curcumin inhibited growth of rhabdomyosarcoma cells (Rh1 and Rh30) (IC50 = 2-5 microM) and arrested cells in G1 phase of the cell cycle. Curcumin also induced apoptosis and inhibited the basal or type I insulin-like growth factor-induced motility of the cells. At physiological concentrations (2.5 microM), curcumin rapidly inhibited phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and Hela). Curcumin also inhibited phosphorylation of Akt in the cells, but only at high concentrations (>40 microM). The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells. Copyright 2006 Wiley-Liss, Inc.

Chemoprevention of nonmelanoma skin cancer.

Authors: Wright TI, Spencer JM, Flowers FP.

Source: J Am Acad Dermatol. 2006 Jun;54(6):933-46; quiz 947-50.Click here to read

Skin cancer is the most common cancer in human beings. The increased incidence of skin cancer has brought much attention to the process by which these tumors develop and how they can be prevented. Efforts have been made to educate the public about the importance of protecting skin from excessive ultraviolet light. Despite this work, the incidence of skin cancer continues to increase. Available compounds may be useful in the chemoprevention of skin cancer. Chemoprevention is defined as oral or topical use of dietary or pharmacologic agents to inhibit or reverse the development of cancer. Potential agents included are the retinoids; difluoromethylornithine; T4 endonuclease V; polyphenolic antioxidants, such as (-)-epigallocatechin gallate, found in green tea and grape seed extract; silymarin; isoflavone genestein; nonsteroidal anti-inflammatory drugs; curcumin; lycopene; vitamin E; beta-carotene; and selenium. Many of these agents are available over the counter as topical or oral preparations.

LEARNING OBJECTIVE: At the conclusion of this activity, participants should be familiar with the chemopreventive agents and their efficacy, as well as any significant side effects associated with them.

Chemical compositions, antioxidant capacities, and antiproliferative activities of selected fruit seed flours.

Authors: Parry J, Su L, Moore J, Cheng Z, Luther M, Rao JN, Wang JY, Yu LL.

Source: J Agric Food Chem. 2006 May 31;54(11):3773-8.Click here to read

Seed flours from black raspberry, red raspberry, blueberry, cranberry, pinot noir grape, and chardonnay grape were examined for their total fat content, fatty acid composition, total phenolic content (TPC), total anthocyanin content (TAC), radical scavenging capacities against the peroxyl (ORAC) and stable DPPH radicals, chelating capacity against Fe(2+), and antiproliferative activities using the HT-29 colon cancer cell line. Significant levels of fat were detected in the fruit seed flours and their fatty acid profiles may differ from those of the respective seed oils. Cranberry seed flour had the highest level of alpha-linolenic acid (30.9 g/100 g fat) and the lowest ratio of n-6/n-3 fatty acids (1.2/1). The ORAC value of the chardonnay seed flour was 1076.4 Trolox equivalents mumol/g flour, and its TPC was 186.3 mg gallic acid equivalents/g flour. These values were 3-12 times higher than the other tested fruit seed flours. Furthermore, the ORAC value was significantly correlated to the TPC under the experimental conditions (P < 0.05). These fruit seed flours also differed in their TAC values and Fe(2+)-chelating capacities. In addition, black raspberry, cranberry, and chardonnay grape seed flour extracts were evaluated for their antiproliferative effects using HT-29 colon cancer cells. All three tested seed flour extracts significant inhibited HT-29 cell proliferation. The data from this study suggest the potential of developing the value-added use of these fruit seed flours as dietary sources of natural antioxidants and antiproliferative agents for optimal human health.

Induction of apoptosis by Cordyceps militaris through activation of caspase-3 in leukemia HL-60 cells.

Authors: Lee H, Kim YJ, Kim HW, Lee DH, Sung MK, Park T.

Source: Biol Pharm Bull. 2006 Apr;29(4):670-4.

Cordyceps militaris is a traditional herbal ingredient frequently used for tonic and medicinal purposes in eastern Asia. The hot water extract of its cultivated fruiting bodies demonstrated a potent cytotoxic effect against the proliferation of the human premyelocytic leukemia cell HL-60, with an IC50 of 0.8 mg/ml for a 12-h treatment. It induced the characteristic apoptotic symptoms in the HL-60 cells, including DNA fragmentation and chromatin condensation, occurring within 12-16 h of treatment at a dose of 1 mg/ml. The activation of caspase-3 and the specific proteolytic cleavage of poly (ADP-ribose) polymerase were detected during the course of apoptosis induction. These results indicate that the hot water extract of Cordyceps militaris fruiting bodies inhibited cancer cell proliferation by inducing cell apoptosis through the activation of caspase-3, and that the Cordyceps militaris extract may therefore have therapeutic potential against human leukemia.

Targeting angiogenesis with integrative cancer therapies.

Authors: Yance DR Jr, Sagar SM.

Source: Integr Cancer Ther. 2006 Mar;5(1):9-29.

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiological pathways that support tumor development while minimizing normal tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The authors will focus on natural health products (NHPs) that have a high degree of antiangiogenic activity but also describe some of their many other interactions that can inhibit tumor progression and reduce the risk of metastasis. NHPs target various molecular pathways besides angiogenesis, including epidermal growth factor receptor (EGFR), the HER-2/neu gene, the cyclooxygenase-2 enzyme, the NF-kB transcription factor, the protein kinases, Bcl-2 protein, and coagulation pathways. The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are confirming the knowledge that is already documented in traditional texts. The following herbs are traditionally used for anticancer treatment and are antiangiogenic through multiple interdependent processes that include effects on gene expression, signal processing, and enzyme activities: Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (turmeric), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinale (ginger), Panax ginseng, Rabdosia rubescens (rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking on clinical trials. More data are required on dose response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as biological response modifiers and adaptogens, potentially enhancing the efficacy of the so-called conventional therapies. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials might be preferred, smaller studies with appropriate end points and surrogate markers for antiangiogenic response could help prioritize agents for the larger resource-intensive phase 3 trials.

The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol.

Authors: Berkson BM, Rubin DM, Berkson AJ.

Source: Integr Cancer Ther. 2006 Mar;5(1):83-9.

The authors describe the long-term survival of a patient with pancreatic cancer without any toxic adverse effects. The treatment regimen includes the intravenous alpha-lipoic acid and low-dose naltrexone (ALA-N) protocol and a healthy lifestyle program. The patient was told by a reputable university oncology center in October 2002 that there was little hope for his survival. Today, January 2006, however, he is back at work, free from symptoms, and without appreciable progression of his malignancy. The integrative protocol described in this article may have the possibility of extending the life of a patient who would be customarily considered to be terminal. The authors believe that life scientists will one day develop a cure for metastatic pancreatic cancer, perhaps via gene therapy or another biological platform. But until such protocols come to market, the ALA-N protocol should be studied and considered, given its lack of toxicity at levels reported. Several other patients are on this treatment protocol and appear to be doing well at this time.

Cancer-treatment-induced bone loss, part 1.

Authors: Michaud LB, Goodin S.

Source: Am J Health Syst Pharm. 2006 Mar 1;63(5):419-30.

PURPOSE: The pathophysiology, frequency, sequelae, diagnosis, and treatment of cancer-treatment-induced bone loss (CTIBL) are discussed.

SUMMARY: CTIBL is a long-term complication associated with cancer therapies that can directly or indirectly affect bone metabolism. Although CTIBL can occur in any patient receiving a cancer therapy known to cause bone loss, CTIBL is most common in patients with breast or prostate cancer who receive chemotherapy, hormone therapy, or surgical castration, as these can cause hypogonadism and induce bone loss. CTIBL causes bone fragility and an increased susceptibility to fractures; therefore, prevention, early diagnosis, and treatment of CTIBL are essential to decrease the risk of fracture. Bone loss occurs more rapidly and tends to be more severe in patients with CTIBL compared with those with normal age-related bone loss. Fractures of the hip, vertebra, and wrist are the fractures most commonly associated with bone loss. CTIBL is diagnosed by measuring bone mass using bone densitometry. Treatment of CTIBL consists of changing diet and lifestyle such as optimizing calcium and vitamin D intake, exercising, modifying behaviors known to increase the risk of CTIBL and pharmacologic therapy with hormone replacement therapy (HRT), selective estrogen-receptor modifiers (SERMs), calcitonin, or a bisphosphonate.

CONCLUSION: Early identification and treatment of CTIBL are essential to prevent fractures. Patients should be instructed to optimize calcium and vitamin D intake, exercise regularly, and modify lifestyle behaviors known to cause bone loss. Patients with CTIBL should be treated with an oral or i.v. bisphosphonate; SERMs or HRT may be an option in some patients if contraindications do not exist.

Caffeine stimulates the proliferation of human lung adenocarcinoma cells and small airway epithelial cells via activation of PKA, CREB and ERK1/2.

Authors: Al-Wadei HA, Takahashi T, Schuller HM.

Source: Oncol Rep. 2006 Feb;15(2):431-5.

The incidence of pulmonary adenocarcinoma (PAC) has increased dramatically over the last three decades. Recent studies have shown that human PAC cells with phenotypic features of bronchiolar Clara cells and experimentally induced PAC of Clara cell origin are under beta-adrenergic growth control. The phosphodiesterase inhibitor, theophylline, which is contained in tea, asthma/allergy medications and numerous dietary supplements selectively stimulated the growth of this cancer type in vivo and in vitro. The current study has tested the hypothesis that another environmentally prominent phosphodiesterase inhibitor, caffeine, has similar effects. Using a cell line derived from a human PAC with Clara cell features (PACC) and immortalized human small airway epithelial cells (SAECs), our data show that caffeine activated protein kinase A (PKA), the mitogen-activated kinases ERK1/2, the nuclear transcription factor cyclic AMP response element binding protein (CREB) and stimulated cell proliferation in these cell lines. These findings suggest that exposure to caffeine may contribute to the prevalence of PAC observed today.

Combined antioxidant ({beta}-carotene, {alpha}-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model.

Authors: Kim Y, Chongviriyaphan N, Liu C, Russell RM, Wang XD.

Source: Carcinogenesis. 2006 Jan 9

Interactions among beta-carotene (BC), alpha-tocopherol (AT), and ascorbic acid (AA) led to the hypothesis that using a combination of these antioxidants could be more beneficial than using a single antioxidant alone, particularly against smoke-related lung cancer. In this investigation, we have conducted an animal study to determine whether combined BC, AT, and AA supplementation (AOX) protects against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis in smoke-exposed (SM) ferrets. Ferrets were treated for six months in the following four groups: a) Control; b) SM + NNK; c) AOX; and d) SM + NNK + AOX. Results showed that the combined AOX supplementation 1) prevented the SM + NNK-decreased lung concentrations of retinoic acid (RA) and BC; 2) inhibited the SM + NNK-induced phosphorylation of Jun N-terminal kinase (JNK), extracellular-signal-regulated protein kinase (ERK), and proliferating cellular nuclear antigen proteins in the lungs of ferrets; and 3) blocked the SM + NNK-induced up-regulation of total p53 and Bax proteins, as well as phosphorylated p53 in the lungs of ferrets. In addition, there were no lesions observed in the lung tissue of ferrets in the control and or the AOX groups after 6 months of intervention, but combined AOX supplementation resulted in a trend toward lower incidence of both preneoplastic lung lesions and lung tumor formation in SM + NNK+AOX group of ferrets, as compared to the SM + NNK group alone. These data indicate that combined AOX supplementation could be a useful chemopreventive strategy against lung carcinogenesis through maintaining normal tissue levels of RA and inhibiting the activation of mitogen-activated protein kinase pathways, cell proliferation, and phosphorylation of p53.

Use of complementary therapies among breast and prostate cancer patients during treatment: a multisite study.

Authors: Hann D. M., Baker F., Roberts C. S., Witt C., McDonald J., Livingston M., Ruiterman J., Ampela R., Crammer C., Kaw O.

Source: Integr Cancer Ther. 2005 Dec;4(4):294-300.

PURPOSE: The purpose of this study was to compare the use of complementary therapies (CT) among breast and prostate cancer patients during active cancer treatment. The authors compared use and beliefs about the role of CT in cancer recovery.

METHODS: A self-report survey was completed by 126 breast cancer patients and 82 prostate cancer patients as part of a multisite research project. The self-report questionnaire inquired about the use of various CTs, sources of information about CT, reasons for using CT, beliefs about the benefits and risks of CT, demographic characteristics, and cancer treatment history.

RESULTS: Most of the respondents were older than 50 years, Caucasian, married, had attended or completed college, and were less than 1 year postdiagnosis. Prostate cancer patients were significantly older than the breast cancer patients (P < .001). Several differences emerged between the groups. Compared to the prostate cancer patients, significantly more of the breast cancer patients reported using CT because they wanted to reduce the risk of recurrence (P < .01), play a more active role in recovery (P < .01), help manage stress (P < .01), take a more holistic approach (P < .01), or boost the immune system (P < .01). More of the prostate cancer patients reported using CT to have more control of their recovery (P < .05). The 2 groups also differed significantly (P < .01) on several beliefs about the potential benefits and risks of using CT.

CONCLUSIONS: Most of the patients in this study had used some form of CT since the time of their diagnosis. Differences among breast and prostate cancer patients with regard to their use of CT during cancer treatment should be considered by oncology professionals who are discussing this topic with their patients.

Phase I study of green tea extract in patients with advanced lung cancer.

Authors: Laurie S.A., Miller V.A., Grant S.C., Kris M.G., Ng K.K.

Source: Cancer Chemother Pharmacol. 2005 Jan;55(1):33-8. Epub 2004 Aug 7.

PURPOSE: Epidemiologic studies suggest that consumption of green tea may have a protective effect against the development of several cancers. Preclinical studies of green tea and its polyphenolic components have demonstrated antimutagenic and anticarcinogenic activity, and inhibition of growth of tumor cell lines and animal tumor models, including lung cancer. Green tea may also have chemopreventive properties, and enhancement of cytotoxicity of chemotherapeutic agents has been demonstrated. This trial was designed to determine the maximum tolerated dose (MTD) of green tea extract (GTE) in patients with advanced lung cancer.

METHODS: A total of 17 patients with advanced lung cancer were registered to receive once-daily oral dosing of GTE at a starting dose of 0.5 g/m2 per day, with an accelerated dose-escalation scheme.

RESULTS: On this schedule, the MTD of GTE was 3 g/m2 per day, and at this dose, GTE was well tolerated with no grade 3 or 4 toxicity seen. Dose-limiting toxicities were diarrhea, nausea and hypertension. No objective responses were seen in this trial. Seven patients had stable disease ranging from 4 to 16 weeks; no patient remained on therapy longer than 16 weeks due to the development of progressive disease.

CONCLUSIONS: This study suggests that while relatively nontoxic at a dose of 3 g/m2 per day, GTE likely has limited activity as a cytotoxic agent, and further study of GTE as a single-agent in established malignancies may not be warranted. Further studies should focus on the potential chemopreventive and chemotherapy-enhancing properties of GTE.

Levels of IL-1 beta control stimulatory/inhibitory growth of cancer cells.

Authors: Roy D, Sarkar S, Felty Q.

Source: Front Biosci. 2006 Jan 1;11:889-98.

Different cellular signaling pathways operate in response to varying levels of IL-1 beta leading to genotoxic damage, cell apoptosis or cell growth. At high levels of IL-1 beta, cells receiving genotoxic insults engage apoptotic pathways. The IL-1 beta over expressing stable MCF7 cell secreting high level of IL-1 beta peptides undergo cell apoptosis. Cotreatment with an inhibitor of IL-1 beta and TNF- alpha synthesis prevented stilbene estrogen-induced lesions. In addition to direct effect of 17 beta-estradiol (E2) on mitochondria and redox cycling of catechol estrogens, E2-induced overexpression of IL-1 beta can produce an increase in the level of ROS. Our recent data showed that MCF7 cell growth and cyclin D1 expression are suppressed by antioxidants and mitochondrial blockers. Stably IL-1 beta transfected cells secreting moderate level of IL-1 beta peptides stimulated the clonal expansion of MCF7 cells. These studies support that in addition to ovarian estrogens, mitogenic signals may also come from TNF- alpha and IL-1 beta-generated O2o- and hydrogen peroxide. Further validation of this concept that the concentrations of the peptide interleukin-1 beta within the cells determine its stimulatory or inhibitory signals regulating the growth of estrogen-dependent tumors might result in novel preventive strategies.

Artesunate in the treatment of metastatic uveal melanoma--first experiences.

Authors: Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G.

Source: Oncol Rep. 2005 Dec;14(6):1599-603.

Artesunate (ART) is a derivative of artemisinin, the active principle of the Chinese herb Artemisia annua L. Artesunate is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile. It has been shown that Artesunate, apart from its anti-malarial activity, has cytotoxic effects on a number of human cancer cell lines, including leukemia, colon cancer and melanoma. We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months. Despite the small number of treated patients, ART might be a promising adjuvant drug for the treatment of melanoma and possibly other tumors in combination with standard chemotherapy. Its good tolerability and lack of serious side effects will facilitate prospective randomized trials in the near future.

An attempt to integrate Western and Chinese medicine: rationale for applying Chinese medicine as chronotherapy against cancer.

Authors: Seki K, Chisaka M, Eriguchi M, Yanagie H, Hisa T, Osada I, Sairenji T, Otsuka K, Halberg F.

Source: Biomed Pharmacother. 2005 Oct;59 Suppl 1:S132-40.

Current Western medical treatment lays its main emphasis on evidence-based medicine (EBM) and cure is assessed by quantifying the effects of treatment statistically. In contrast, in Chinese medicine, cure is generally assessed by evaluating the patient's "pattern" (Zheng) [cf. Glossary] and medicines are prescribed according to this. We believe that traditional Chinese medicine (TCM) cannot be evaluated precisely according to Western principles, in which a constant amount of the same medicine is given to a group of patients to be evaluated. When assessing cure using TCM, Zheng is more important than the determination of medical effects. This means that quantitative evaluation of TCM treatment can be very difficult. In this paper, we focused on the Yin-Yang [cf. Glossary]balance to determine Zheng, and at the same time attempted to determine the treatment effects by applying the concept of regulation of Yin-Yang according to chronotherapeutic principles. According to Zheng, advanced cancer patients generally lack both Yin and Yang. Chinese medical treatment therefore seeks to supplement both Yin and Yang. However, we divided patients into two groups and compared them with respect to survival. One group was administered a predominantly Yang (Qi) [cf. Glossary] tonic herbal treatment during the daytime, while the other group was administered Yin (Blood) [cf. Glossary] tonics during night time. A comparison of the results of treatment showed that the patients in the group receiving Yang (Qi) replenishment during the daytime lived longer than patients receiving Yin (Blood) nourishment during the night. Moreover, the patients in the daytime Yang (Qi) replenishment group also fared significantly better than patients treated solely by Western methods.

Vegetables affect the expression of genes involved in carcinogenic and anticarcinogenic processes in the lungs of female C57BL/6 mice.

Authors: van Breda SG, van Agen E, van Sanden S, Burzykowski T, Kleinjans JC, Delft JH.

Source: J Nutr. 2005 Nov;135(11):2546-52.

Worldwide, lung cancer is the most prevalent and lethal malignant disease. In addition to avoidance of the most predominant risk factor, i.e., tobacco use, consumption of high amounts of vegetables and fruits could be an effective means of preventing lung cancer. However, the molecular mechanisms underlying lung cancer risk reduction by vegetables are not clear. In the present study, the effect of vegetables on gene expression changes in the lungs of female C57Bl/6 mice was investigated using cDNA microarray technology. The mice were fed 1 of 8 diets for 2 wk: a control diet containing no vegetables (diet 1); a diet containing a vegetable mixture at 100 (diet 2, 10% dose), 200 (diet 3, 20% dose), or 400 (diet 4, 40% dose) g/kg; or a diet containing cauliflower at 70 (diet 5, 7% dose); carrots at 73 (diet 6, 7.3% dose); peas at 226 (diet 7, 22.6% dose); or onions at 31 (diet 8, 3.1% dose) g/kg. The vegetable mixture consisted of these 4 individual vegetables. After the mice were killed, the lungs were removed and total RNA was isolated from the lungs for expression analysis of 602 genes involved in pathways of (anti)-carcinogenesis. The results of this study suggest that individual vegetables have a higher potential of modulating genes (5 from the 8 modulated genes) in favor of lung cancer risk prevention, in comparison with the vegetable mixture (2 from the 7 modulated genes); the other gene modulations are expected to enhance lung cancer risk. The pathways involved were miscellaneous and included cell growth, apoptosis, biotransformation, and immune response. Furthermore, carrots were able to modulate most gene expressions, and most of these effects occurred in processes that favored lung cancer risk prevention. The current study provides more insight into the genetic mechanisms by which vegetables, in particular carrots, can prevent lung cancer risk.

The role of PSA in diagnosis of prostate cancer and its recurrence.

Authors: Vergho DC, Heine K, Wolff JM.

Source: Pathologe. 2005 Nov;26(6):473-8.

Prostate specific antigen is the most important tumor marker of prostate cancer. PSA, in conjunction with digital rectal examination, is the first-line clinical tool for detection of prostate cancer. To improve its specifity PSA-density, PSA-ratio (fPSA/tPSA), PSA-velocity, and complexed PSA have been introduced into clinical praxis. The treatment of lower stage disease in younger men has resulted in a longer period of post-treatment cancer surveillance. Biochemical recurrence is an early indicator for clinical disease recurrence. PSA doubling time allows to distinguish between local and systemic progression and is also a valid predictor for distant metastasis and death of disease.

Dietary components modify gene expression: implications for carcinogenesis.

Authors: Yang K, Yang W, Mariadason J, Velcich A, Lipkin M, Augenlicht L.

Source: J Nutr. 2005 Nov;135(11):2710-4.

Mouse genetic models that probe important pathways in intestinal cell maturation, such as cell-cycle regulation, apoptosis, and, especially, lineage specific differentiation, have provided profound insight into the underlying mechanisms of intestinal tumor formation and progression. However, a wealth of epidemiological and experimental data indicates that environment, especially the diet, is a principal determinant of relative risk for tumor development. We have demonstrated that even in mouse models in which tumor incidence is strongly initiated by genetic manipulation of genes, such as Apc, p21(WAF1/cip1), and p27(Kip1), a Western-style diet that is high in fat and low in calcium and vitamin D can dramatically increase and accelerate tumor formation. Moreover, experiments show that modulation of calcium and vitamin D levels can substantially influence tumor formation in both the mouse genetic models, as well as in a new dietary model that appears to mimic the development of sporadic colon cancer. Finally, analysis of gene expression profiles provides important insights into how diets may alter metabolic profiles and regulatory pathways that influence probability of tumor formation in the histologically and physiologically normal intestinal mucosa.

Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angiogenesis.

Authors: Roomi MW, Roomi N, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.

Source: Oncol Rep. 2005 Oct;14(4):807-15.

Degradation of extracellular matrix (ECM) is a hallmark of tumor invasion, metastasis and angiogenesis. Based on the Rath multitargeted approach to cancer using natural substances to control ECM stability and enhancing its strength, we developed a novel formulation (NM) of lysine, proline, ascorbic acid and green tea extract that has shown significant anti-cancer activity against a number of cancer cell lines. The aim of the present study was to determine whether NM exhibits anti-angiogenic and anti-metastatic effects using in vitro and in vivo experimental models. Angiogenesis was measured using a chorioallantoic membrane (CAM) assay in chick embryos and bFGF-induced vessel growth in C57BL/6J female mice. To determine the in vivo effect of NM on the tumor xenograft growth, male nude mice were inoculated with 3 x 10(6) MNNG-HOS cells. Control mice were fed a mouse chow diet, while the test group was fed a mouse chow diet supplemented with 0.5% NM for 4 weeks. In vitro studies on cell proliferation (MTT assay), MMP expression (zymography) and Matrigel invasion were conducted on human osteosarcoma U2OS, maintained in McCoy medium, supplemented with 10% FBS, penicillin and streptomycin in 24-well tissue culture plates and tested with NM at 0, 10, 50, 100, 500, and 1000 microg/ml in triplicate at each dose. NM at 250 microg/ml caused a significant (p<0.05) reduction in bFGF-induced angiogenesis in CAM. NM inhibited tumor growth of osteosarcoma MNNG-HOS cell xenografts in nude mice by 53%; furthermore, tumors in NM-treated mice were less vascular and expressed lower levels of VEGF and MMP-9 immunohistochemically than tumors in the control group. In addition, NM exhibited a dose-dependent inhibition of osteosarcoma U2OS cell proliferation (up to 60% at 1000 microg/ml), MMP-2 and -9 expression (with virtual total inhibition at 500 microg/ml NM), and invasion through Matrigel (with total inhibition at 100 microg/ml NM). Moreover, NM decreased U2OS cell expression of VEGF, angiopoietin-2, bFGF, PDGF and TGFbeta-1. These results together with our earlier findings suggest that NM is a relatively non-toxic formulation, which inhibits growth, invasion, metastasis, and angiogenesis of tumor cells.

Targeted treatment of cancer with artemisinin and artemisinin-tagged iron-carrying compounds.

Authors: Lai H, Sasaki T, Singh NP.

Source: Expert Opin Ther Targets. 2005 Oct;9(5):995-1007.

Artemisinin is a chemical compound that reacts with iron to form free radicals which can kill cells. Cancer cells require and uptake a large amount of iron to proliferate. They are more susceptible to the cytotoxic effect of artemisinin than normal cells. Cancer cells express a large concentration of cell surface transferrin receptors that facilitate uptake of the plasma iron-carrying protein transferrin via endocytosis. By covalently tagging artemisinin to transferrin, artemisinin could be selectively picked up and concentrated by cancer cells. Futhermore, both artemisinin and iron would be transported into the cell in one package. Once an artemisinin-tagged transferrin molecule is endocytosed, iron is released and reacts with artemisinin moieties tagged to transferrin. Formation of free radicals kills the cancer cell. The authors have found that artemisinin-tagged transferrin is highly selective and potent in killing cancer cells. Thus, artemisinin and artemisinin-tagged iron-carrying compounds could be developed into powerful anticancer drugs.

Diet and bladder cancer: a case-control study.

Authors: Radosavljevic V, Jankovic S, Marinkovic J, Dokic M.

Source: Int Urol Nephrol. 2005;37(2):283-9.

To investigate possible relationships between diet and risk for bladder cancer in Serbia, the hospital-based case-control study was carried out. This study included 130 newly diagnosed bladder cancer patients and the same number of controls matched by sex, age (%+/-%2 years) and type of residence (rural or urban). Dietary information was obtained by using a food frequency questionnaire. Initial case-control comparisons were based on tertiles of average daily intake of control group. The odds ratios (ORs) were computed for each tertile, with the lowest tertile defined as the referent category. All variables (food items) significantly related to bladder cancer were included in multivariable logistic regression analysis. According to this analysis, risk factors for bladder cancer appeared to be consumption of liver (OR=6.60, 95%CI=1.89-23.03), eggs (OR=3.12, 95%CI=1.10-8.80), pork (OR=2.99, 95%CI=1.16-7.72), and pickled vegetable (OR=3.25, 95%CI=1.36-7.71). A protective effect was found for dietary intake of kale (OR=0.21, 95%CI=0.06-0.73), cereals (OR=0.19, 95%CI=0.06-0.62), tangerines (OR=0.21, 95%CI=0.07-0.68), cabbage (OR=0.27, 95% CI=0.11-0.68), and carrots (OR=0.15, 95%CI=0.05-0.41). The study indicated a potentially important role for dietary fat and pickled vegetables in bladder carcinogenesis. An inverse association was recorded between consumption of fruits, vegetables and cereals, and the development of bladder cancer.

Cancer prevention by phytochemicals.

Authors: Nishino H, Murakoshi M, Mou XY, Wada S, Masuda M, Ohsaka Y, Satomi Y, Jinno K.

Source: Oncology. 2005;69 Suppl 1:38-40. Epub 2005 Sep 19.

Information has been accumulated indicating that diets rich in vegetables and fruits can reduce the risk of a number of chronic diseases, including cancer, cardiovascular disease, diabetes and age-related macular degeneration. Phytochemicals (various factors in plant foods), such as carotenoids, antioxidative vitamins, phenolic compounds, terpenoids, steroids, indoles and fibers, have been considered responsible for the risk reduction. Among them, a mixture of natural carotenoids has been studied extensively and proven to show beneficial effects on human cancer prevention. Copyright (c) 2005 S. Karger AG, Basel.

Lycopene Inhibits Cell Migration and Invasion and Upregulates Nm23-H1 in a Highly Invasive Hepatocarcinoma, SK-Hep-1 Cells.

Authors: Huang CS, Shih MK, Chuang CH, Hu ML.

Source: J Nutr. 2005 Sep;135(9):2119-23.

The carotenoid lycopene has been associated with decreased risks of several types of cancer, such as prostate cancer and hepatoma. Tumor metastasis is the most important cause of cancer death. Although lycopene was shown to inhibit metastasis, the mechanism underlying this action is not well understood. Here, we tested the possibility that lycopene may inhibit cancer cell metastasis by upregulating the expression of nm23-H1, a metastasis suppressor gene, in SK-Hep-1 cells, a highly invasive hepatoma cell line, and we determined migration and invasion activities and the expression of nm23-H1 protein and mRNA. We showed that lycopene inhibited SK-Hep-1 migration and invasion in a bell-shaped manner, with the highest effect at 5 mumol/L (91 and 63% inhibition for migration and invasion, respectively; P < 0.05). At the same test level (10 mumol/L), lycopene was much more effective than beta-carotene in reducing cell invasion (by approximately 870%). In contrast to the effects on migration and invasion, lycopene enhanced nm23-H1 expression at both the protein and mRNA levels; the effects were also bell shaped, and at 5 mumol/L, lycopene enhanced nm23-H1 protein and mRNA expressions by 220 +/- 33 and 153 +/- 22% (P < 0.01), respectively. These bell-shaped effects of lycopene may be related to autoxidation of lycopene at elevated concentrations (>/=10 mumol/L). Significant correlations existed between nm23-H1 protein expression and migration (r(2) = 0.78, P < 0.001) and between nm23-H1 protein expression and invasion (r(2) = 0.84, P < 0.001) in lycopene-treated SK-Hep-1 cells. We conclude that lycopene has significant antimigration and anti-invasion activity, and that this effect is associated with its induction of nm23-H1 expression.

Dance as a therapy for cancer prevention.

Authors: Aktas G, Ogce F.

Source: Asian Pac J Cancer Prev. 2005 Jul-Sep;6(3):408-11.

Even though the field of medicine has developed tremendously, the wide variety of cancer is still among chronic and life threatening disease today. Therefore, the specialists constantly research and try every possible way to find cure or preventive ways to stop its further development. For this reason, studies concerning the chronic disease such as cancer have been spread to many different fields. In this regard, many other alternative ways besides medicine, are used in prevention of cancer. Nutritional therapy, herbal therapy, sportive activities, art therapy, music therapy, dance therapy, imagery, yoga and acupuncture can be given as examples. Among these, dance/movement therapy which deals with individuals physical, emotional, cognitive as well as social integration is widely used as a popular form of physical activity. The physical benefits of dance therapy as exercise are well documented. Studies have shown that physical activity is known to increase special neurotransmitter substances in the brain (endorphins), which create a state of well-being. And total body movement such as dance enhances the functions of other body systems, such as circulatory, respiratory, skeletal, and muscular systems. Regarding its unique connection to the field of medicine, many researches have been undertaken on the effects of dance/movement therapy in special settings with physical problems such as amputations, traumatic brain injury, and stroke, chronic illnesses such as anorexia, bulimia, cancer, Alzheimer's disease, cystic fibrosis, heart disease, diabetes, asthma, AIDS, and arthritis. Today dance/movement therapy is a well recognized form of complementary therapy used in hospitals as well as at the comprehensive clinical cancer centres.

Molecular characterization of Coriolus versicolor PSP-induced apoptosis in human promyelotic leukemic HL-60 cells using cDNA microarray.

Authors: Zeng F, Hon CC, Sit WH, Chow KY, Hui RK, Law IK, Ng VW, Yang XT, Leung FC, Wan JM.

Source: Int J Oncol. 2005 Aug;27(2):513-23.

Proteins and peptide bound polysaccharides (PSP) extracted from Basidiomycetous fungi are widely used in cancer immunotherapy and recently demonstrated to induce apoptosis in cancer cells in vitro. In order to provide the molecular pharmacological mechanisms of PSP on human cancer cells, we investigated the gene expression profiles of PSP-treated apoptotic human promyelotic leukemic HL-60 cells using ResGen 40k IMAGE printed cDNA microarray. In total 378 and 111 transcripts were identified as differentially expressed in the apoptotic cells by at least a factor of 2 or 3, respectively. Our data show that PSP-induced apoptosis in HL-60 cells might be mediated by up-regulation of early transcription factors such as AP-1, EGR1, IER2 and IER5, and down-regulation of NF-kB transcription pathways. Other gene expression changes, including the increase of several apoptotic or anti-proliferation genes, such as GADD45A/B and TUSC2, and the decrease of a batch of phosphatase and kinase genes, may also provide further evidences in supporting the process of PSP induced apoptosis in cancer cells. Some of the well-characterized carcinogenesis-related gene transcripts such as SAT, DCT, Melan-A, uPA and cyclin E1 were also alternated by PSP in the HL-60 cells. These transcripts can be employed as markers for quality control of PSP products on functional levels. The present study provides new insight into the molecular mechanisms involved in PSP-induced apoptosis in leukemic HL-60 cells analyzed by cDNA microarray.

Prospects for cancer control: colorectal cancer.

Authors: Cox B, Sneyd M.

Source: N Z Med J. 2005 Aug 26;118(1221):U1632.

AIMS: The study assessed the contribution to the control of colorectal cancer achievable from primary prevention, screening, early diagnosis, and treatment in New Zealand.

METHODS: Available estimates of the attributable risk or protection offered by significantly increasing consumption of fruit and vegetables were used to predict the number of cases of (and deaths from) colorectal cancer prevented if these activities were effective in 1999. The potential effect of screening was also estimated from published results. Estimates of the potential effect of improvements in early diagnosis and treatment available from cancer-control plans of other countries were used to estimate the likely impact of such improvements in New Zealand.

RESULTS: Primary prevention could potentially prevent 81 deaths in men and 77 deaths in women from colorectal cancer each year. The potential impact of screening differed between screening methods, with the prevention of 44 deaths in men and 35 deaths in women from colorectal cancer by screening using faecal occult blood testing or 73 deaths in men and 53 deaths in women annually from colorectal cancer by screening using flexible sigmoidoscopy. Improvements in surgical practice and reorganisation of surgical services together with improved use of radiotherapy and chemotherapy could prevent about 82 deaths in men and 78 deaths in women from colorectal cancer each year.

CONCLUSIONS: The most immediate control of colorectal cancer appeared to be achievable by improvements in surgical services and the introduction of screening while increased consumption of fruit and vegetables provided potential longer-term reductions in colorectal cancer incidence and mortality.

Screening of biological activities present in honeybee (Apis mellifera) royal jelly.

Authors: Salazar-Olivo LA, Paz-Gonzalez V.

Source: Toxicol In Vitro. 2005 Aug;19(5):645-51.

Bioactivities present in three honeybee royal jelly (RJ) protein fractions were screened for diverse in vitro model systems. RJCP, a RJ crude protein extract, stimulated cell growth of Tn-5B1-4 insect cells inducing 6.5 population doublings per mg of protein added to culture medium, meanwhile fetal bovine serum, the usual growth supplement, gave rise only to 2.55 population doublings. RJCP, as well as the fractions RJP30 and RJP60 obtained by precipitation with ammonium sulfate, also affected Tn-5B1-4 cell shape and stimulated adhesion of these cells to the substrate. RJP30 also increased the percent of mature adipocytes in cultures of 3T3-F442A murine preadipocytes twofold with respect to insulin treatment, without inducing additional cell growth of confluent preadipocytes. Fractions RJCP and RJP60 showed similar capacity as that of insulin to stimulate the formation of mature 3T3 adipocytes. Fraction RJP30 also was cytotoxic for HeLa human cervicouterine carcinoma cells, diminishing 2.5-fold the initial cell density after seven days of treatment. Our results show the presence of diverse bioactivities in RJ affecting cell growth, cell differentiation and cell survival of insect, murine, and human cancer cells.

Dehydrotrametenolic acid selectively inhibits the growth of H-ras transformed rat2 cells and induces apoptosis through caspase-3 pathway.

Authors: Kang HM, Lee SK, Shin DS, Lee MY, Han DC, Baek NI, Son KH, Kwon BM.

Source: Life Sci. 2005 Aug 18

The screening of natural products that preferentially inhibit growth of H-ras transformed rat2 cells vs. rat2 cells was performed to identify H-ras specific growth inhibitor. A lanostane-type triterpene acid, dehydrotrametenolic acid (3beta-hydroxylanosta-7,9(11),24-trien-21-oic acid), was isolated from the sclerotium of Poria cocos (Polyporaceae). Dehydrotrametenolic acid selectively inhibited the growth of H-ras transformed cells with a GI(50) value of 40 muM. FACS analysis indicated that the compound exerted its anti-proliferation effects through cell cycle arrest at G2/M phase and accumulation of sub-G1 population. Dehydrotrametenolic acid-induced apoptosis was further confirmed with chromosomal DNA fragmentation, caspase-3 activation, and degradation of PARP and Lamin A/C degradation. The compound also regulated the expression of H-ras, Akt and Erk, which are the downstream proteins of H-ras signaling pathways. The results suggest that dehydrotrametenolic acid can be a potential anticancer agent against H-ras transformed tumor.

Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance.

Authors: Harrison JF, Hollensworth SB, Spitz DR, Copeland WC, Wilson GL, LeDoux SP

Source: Nucleic Acids Res. 2005 Aug 17;33(14):4660-71. Print 2005.

Neurodegeneration can occur as a result of endogenous oxidative stress. Primary cerebellar granule cells were used in this study to determine if mitochondrial DNA (mtDNA) repair deficiencies correlate with oxidative stress-induced apoptosis in neuronal cells. Granule cells exhibited a significantly higher intracellular oxidative state compared with primary astrocytes as well as increases in reductants, such as glutathione, and redox sensitive signaling molecules, such as AP endonuclease/redox effector factor-1. Cerebellar granule cultures also exhibited an increased susceptibility to exogenous oxidative stress. Menadione (50 muM) produced twice as many lesions in granule cell mtDNA compared with astrocytes, and granule cell mtDNA repair was significantly less efficient. A decreased capacity to repair oxidative mtDNA damage correlates strongly with mitochondrial initiated apoptosis in these neuronal cultures. Interestingly, the mitochondrial activities of initiators for base excision repair (BER), the bifunctional glycosylase/AP lyases as well as AP endonuclease, were significantly higher in cerebellar granule cells compared with astrocytes. The increased mitochondrial AP endonuclease activity in combination with decreased polymerase gamma activity may cause an imbalance in oxidative BER leading to an increased production and persistence of mtDNA damage in neurons when treated with menadione. This study provides evidence linking neuronal mtDNA repair capacity with oxidative stress-related neurodegeneration.

Combination of S-allylcysteine and lycopene induces apoptosis by modulating Bcl-2, Bax, Bim and caspases during experimental gastric carcinogenesis.

Authors: Velmurugan B, Mani A, Nagini S.

Source: Eur J Cancer Prev. 2005 Aug;14(4):387-93.

Combination chemoprevention by diet-derived agents that induce apoptosis is a promising strategy to control gastric cancer, the second most common malignancy worldwide. The present study was undertaken to investigate the apoptosis-inducing potential of a combination of S-allylcysteine (SAC), an organosulphur constituent of garlic and lycopene, a tomato carotenoid during N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) and saturated sodium chloride (S-NaCl)-induced gastric carcinogenesis in Wistar rats using the apoptosis-associated proteins Bcl-2, Bax, Bim, caspase 8 and caspase 3 as markers. Animals administered MNNG followed by S-NaCl developed squamous cell carcinomas of the stomach associated with increased Bcl-2 expression and decreased expression of Bax, Bim, caspase 8 and caspase 3. Although SAC and lycopene alone significantly suppressed the development of gastric cancer, administration of SAC and lycopene in combination was more effective in inhibiting MNNG-induced stomach tumours and modulating the expression of apoptosis-associated proteins. Our results suggest that induction of apoptosis by SAC and lycopene combination represents one of the possible mechanisms that could account for their synergistic chemopreventive activity against gastric cancer.

Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years.

Authors: Christenson LJ, Borrowman TA, Vachon CM, Tollefson MM, Otley CC, Weaver AL, Roenigk RK.

Source: JAMA. 2005 Aug 10;294(6):681-90.

CONTEXT: The incidence of nonmelanoma skin cancer is increasing rapidly among elderly persons, but little is known about its incidence in the population younger than 40 years.

OBJECTIVES: To estimate the sex- and age-specific incidences of basal cell carcinoma and squamous cell carcinoma in persons younger than 40 years in Olmsted County, Minnesota, and to evaluate change in incidence over time; to describe the clinical presentation, rate of recurrence and metastasis, and histologic characteristics of these tumors in this population-based sample.

DESIGN: Population-based retrospective incidence case review.

SETTING: Residents of Olmsted County, Minnesota, a population with comprehensive medical records captured through the Rochester Epidemiology Project.

PARTICIPANTS: Patients younger than 40 years with basal cell carcinoma or squamous cell carcinoma diagnosed between 1976 and 2003.

MAIN OUTCOME MEASURES: Incident basal cell carcinomas and squamous cell carcinomas and change in incidence of these tumors over time.

RESULTS: During the study period, 451 incident basal cell carcinomas were diagnosed in 417 patients and 70 incident squamous cell carcinomas were diagnosed in 68 patients. Of these tumors, 328 were histologically confirmed basal cell carcinomas and 51 were histologically confirmed squamous cell carcinomas. Overall, the age-adjusted incidence of basal cell carcinoma per 100,000 persons was 25.9 (95% confidence interval [CI], 22.6-29.2) for women and 20.9 (95% CI, 17.8-23.9) for men. The incidence of basal cell carcinoma increased significantly during the study period among women (P<.001) but not men (P = .19). Nodular basal cell carcinoma was the most common histologic subtype; 43.0% of tumors were solely nodular basal cell carcinoma and 11.0% had a mixed composition, including the nodular subtype. The incidence of squamous cell carcinoma was similar in men and women, with an average age- and sex-adjusted incidence per 100 000 persons of 3.9 (95% CI, 3.0-4.8); the incidence of squamous cell carcinoma increased significantly over the study period among both women (P = .01) and men (P = .04).

CONCLUSIONS: This population-based study demonstrated an increase in the incidence of nonmelanoma skin cancer among young women and men residing in Olmsted County, Minnesota. There was a disproportionate increase in basal cell carcinoma in young women. This increase may lead to an exponential increase in the overall occurrence of nonmelanoma skin cancers over time as this population ages, which emphasizes the need to focus on skin cancer prevention in young adults.

Immunomodulatory and antitumour effects of an exopolysaccharide fraction from cultivated Cordyceps sinensis (Chinese caterpillar fungus) on tumour-bearing mice.

Authors: Zhang W, Yang J, Chen J, Hou Y, Han X.

Source: Biotechnol Appl Biochem. 2005 Aug;42(Pt 1):9-15.

Cordyceps sinensis (Chinese caterpillar fungus) is a fungus parasitic on the larvae of Lepidoptera and has been considered to be a precious tonic food and herbal medicine since ancient times in China. Recently, some fungal strains have been isolated from the fruiting bodies of wild C. sinensis, and some of them have been reported to show the same properties as the natural product. In the present study, an EPSF (exopolysaccharide fraction) was prepared from cultivated C. sinensis and its effects on B16 melanoma-bearing mice were investigated. Three doses of EPSF were intraperitoneally administered every 2 days after the day of tumour-cell injection. The experiment was terminated on day 28. Phagocytosis of peritoneal macrophages and proliferation of spleen and thymus lymphocytes were assayed. The tumour metastatic foci on the lung and liver surface were checked. The expression of oncoprotein Bcl-2 in livers and lungs was assayed by a immunohistochemical method. The results showed that EPSF significantly enhanced the Neutral Red uptake capacity of peritoneal macrophages (60 mg/kg, P<0.01; 120 mg/kg, P<0.001) and spleen lymphocyte proliferation (60 mg/kg, P<0.05; 120 mg/kg, P<0.001) in B16-bearing mouse. The metastasis of B16 melanoma cells to lungs (120 mg/kg) and livers (30, 60 and 120 mg/kg) was significantly inhibited by EPSF. Moreover, EPSF decreased the levels of Bcl-2 in the lungs (120 mg/kg) and livers (30, 60 and 120 mg/kg). These results suggest that EPSF has immunomodulatory function and antitumour activity.

Rituximab therapy of lymphoma is enhanced by orally administered (1-->3),(1-->4)-D-beta-glucan.

Authors: Modak S, Koehne G, Vickers A, O'Reilly RJ, Cheung NK.

Source: Leuk Res. 2005 Jun;29(6):679-83.

By activating complement, antitumor monoclonal antibodies coat tumor cells with iC3b. beta-glucans, naturally occurring glucose polymers, bind to the lectin domain of the leukocyte receptor CR3, prime it for binding to iC3b, and trigger cytotoxicity of iC3b-coated tumor cells. We studied the combination of the complement-activating antibody rituximab with barley-derived (1-->3),(1-->4)-beta-D-glucan (BG) against CD-20 positive lymphoma xenografts in SCID mice. Growth of established subcutaneous non-Hodgkin's lymphoma (NHL) (Daudi and EBV-derived B-NHL) or Hodgkin's disease (Hs445 and RPMI6666) was significantly suppressed in mice treated with a combination of intravenous rituximab and oral BG, when compared to mice treated with rituximab or BG alone. Survival of mice with disseminated lymphoma was significantly increased in the combination group as compared to other treatment groups. No clinical toxicity was observed. The therapeutic efficacy and lack of toxicity of this combination supports further investigation into its clinical utility.

Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case-control study nested in the JACC Study.

Authors: Ito Y, Wakai K, Suzuki K, Ozasa K, Watanabe Y, Seki N, Ando M, Nishino Y, Kondo T, Ohno Y, Tamakoshi A; JACC Study Group.

Source: J Epidemiol. 2005 Jun;15 Suppl 2:S140-9.

BACKGROUND: Lung cancer mortality is inversely associated with high serum carotenoid levels and high intake of vegetables and fruits rich in carotenoids. The Japan Collaborative Cohort (JACC) Study was conducted to investigate whether serum levels of carotenoids, retinol, tocopherols, and folic acid were associated with risk for lung cancer death with follow-up through 1997. To examine the association by sex, we extended the follow-up and analyzed additional serum samples.

METHODS: In the JACC Study, 39,242 subjects provided serum samples at baseline between 1988 and 1990. We identified 211 cases (163 men and 48 women) of death from lung cancer during about 10-year follow-up ending in 1999. Of the subjects who survived to the end of that follow-up, 487 controls (375 men and 112 women) were selected, and were matched to each case of lung cancer death for sex, age and participating institution. We measured serum levels of antioxidants in cases of lung cancer death and controls. Odds ratio (OR) for lung cancer death was estimated using conditional logistic models by sex.

RESULTS: For men, the risk of lung cancer death was significantly lower for the highest quartile of serum alpha- and beta-carotenes, lycopene, and beta-cryptoxanthin than for the lowest quartile: the OR adjusted for smoking and other covariates were 0.41, 0.28, 0.46, and 0.39, respectively. For women, serum levels of alpha-carotene and zeaxanthin/lutein were inversely associated with risk of lung cancer, but the association was not significant. No association between lung cancer and serum levels of beta-carotene, beta-cryptoxanthin, and retinol was appeared among women. There was a suggestion that association between lung cancer and high serum levels of these components might differ between men and women.

CONCLUSIONS: Higher serum levels of carotenoids appear to play a role in preventing death from lung cancer among Japanese men. Relationships between lung cancer and serum levels of some carotenoids appear to differ between sexes. However, further study with a large number of women cases needs to clarify the discrepancy between sexes.

Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells.

Authors: Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP.

Source: Biochem Pharmacol. 2005 May 15;69(10):1421-32.

It has been shown that proteasome activity is required for cancer cell survival and consumption of fruits and vegetables is associated with decreased cancer risk. Previously, we reported that grape extract could inhibit proteasome activity and induce apoptosis in tumor cells. In this study, we examined the flavonoids apigenin, quercetin, kaempferol and myricetin for their proteasome-inhibitory and apoptosis-inducing abilities in human tumor cells. We report that apigenin and quercetin are much more potent than kaempferol and myricetin at: (i) inhibiting chymotrypsin-like activity of purified 20S proteasome and of 26S proteasome in intact leukemia Jurkat T cells; (ii) accumulating putative ubiquitinated forms of two proteasome target proteins, Bax and Inhibitor of nuclear factor kappabeta-alpha in Jurkat T cells and (iii) inducing activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in Jurkat T cells. The proteasome-inhibitory abilities of these compounds correlated with their apoptosis-inducing potencies. Results from computational modeling of the potential interactions of these flavonoids to the chymotrypsin site (beta5 subunit) of the proteasome were consistent with the obtained proteasome-inhibitory activities. We found that the C(4) carbon may be a site of nucleophilic attack by the OH group of N-terminal threonine of proteasomal beta5 subunit and that the C(3) hydroxyl may alter the ability of these flavonoids to inhibit the proteasome. Finally, apigenin neither effectively inhibited the proteasome activity nor induced apoptosis in non-transformed human natural killer cells. Our results suggested that the proteasome may be a target of these dietary flavonoids in human tumor cells and that inhibition of the proteasome by flavonoids may be one of the mechanisms responsible for their cancer-preventive effects.

Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells.

Authors: Ma Z, Otsuyama K, Liu S, Abroun S, Ishikawa H, Tsuyama N, Obata M, Li FJ, Zheng X, Maki Y, Miyamoto K, Kawano MM.

Source: Blood. 2005 Apr 15;105(8):3312-8. Epub 2004 Dec 30.

In the search for a more effective adjuvant therapy to treat multiple myeloma (MM), we investigated the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du-Tang (HLJDT), Gui-Zhi-Fu-Ling-Wan (GZFLW), and Huang-Lian-Tang (HLT) on the proliferation and apoptosis of myeloma cells. HLJDT inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially MPC-1(-) immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3. Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect of HLJDT on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin. Baicalein as well as baicalin suppressed the survival in vitro of MPC-1(-) immature myeloma cells rather than MPC-1(+) myeloma cells from myeloma patients. Baicalein inhibited the phosphorylation of IkB-alpha, which was followed by decreased expression of the IL-6 and XIAP genes and activation of caspase-9 and caspase-3. Therefore, HLJDT and Scutellaria radix have an antiproliferative effect on myeloma cells, especially MPC-1(-) immature myeloma cells, and baicalein may be responsible for the suppressive effect of Scutellaria radix by blocking IkB-alpha degradation. (Blood. 2005;105:3312-3318).

Inhibitory effects of polysaccharides isolated from Phellinus gilvus on benzo(a)pyrene-induced forestomach carcinogenesis in mice.

Authors: Bae JS, Jang KH, Yim H, Park SC, Jin HK.

Source: World J Gastroenterol. 2005 Jan 28;11(4):577-9.

AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study.

METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4, PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis.

RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk.

CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.

Selective induction of apoptosis in murine skin carcinoma cells (CH72) by an ethanol extract of Lentinula edodes.

Authors: Gu YH, Belury MA.

Source: Cancer Lett. 2005 Mar 18;220(1):21-8.

The effects of ethanol extracts from four species of mushroom fruiting bodies, mushroom spores and mushroom cultured broth, were assessed for modulation of cell proliferation and apoptosis in murine skin carcinoma cells (CH72) and non-tumorigenic epidermal cells (C50). While extracts from mycelia of Grifola frondosa, Ganoderma lucidum, Hericium erinaceus, or from spores of G. lucidum exerted little, if any, effect on proliferation, the ethanol-soluble extract of Lentinula edodes (L. edodes) significantly decreased cell proliferation of CH72 cells. There were no changes in the proliferative response of the non-tumorigenic keratinocyte cell line, C50, to any of the mushroom extracts tested. To analyze cell proliferation and apoptosis, fluorescent DNA-microscopy with ethidium bromide and acridine orange staining of cells revealed L. edodes reduced cell proliferation and induced apoptosis in time- and dose-dependent manners in carcinoma cells but had no effect in non-tumorigenic cells (C50). Cell cycle analysis demonstrated that L. edodes extract induced a transient G(1) arrest, with no changes observed in the non-tumorigenic cells (C50).

Dietary intake of lycopene is associated with reduced pancreatic cancer risk.

Authors: Nkondjock A, Ghadirian P, Johnson KC, Krewski D; Canadian Cancer Registries Epidemiology Research Group.

Source: J Nutr. 2005 Mar;135(3):592-7.

Although fruits and vegetables have been implicated in the etiology of pancreatic cancer, the role of phytochemicals in these food groups has received little attention to date. In this study, we investigated the possible association between dietary carotenoids and pancreatic cancer risk. A case-control study of 462 histologically confirmed pancreatic cancer cases and 4721 population-based controls in 8 Canadian provinces took place between 1994 and 1997. Dietary intake was assessed by a self-administered FFQ. Unconditional logistic regression was used to assess associations between specific and total carotenoid intakes and the risk of pancreatic cancer. All tests of statistical significance were 2-sided. After adjustment for age, province, BMI, smoking, educational attainment, dietary folate, and total energy intake, lycopene, provided mainly by tomatoes, was associated with a 31% reduction in pancreatic cancer risk among men [odds ratio (OR) = 0.69; 95% CI: 0.46-0.96; P = 0.026 for trend] when comparing the highest and lowest quartiles of intake. Both beta-carotene (OR = 0.57; 95% CI: 0.32-0.99; P = 0.016 for trend) and total carotenoids (OR = 0.58; 95% CI: 0.34-1.00; P = 0.02 for trend) were associated with a significantly reduced risk among those who never smoked. The results of this study suggest that a diet rich in tomatoes and tomato-based products with high lycopene content may help reduce pancreatic cancer risk.

Pilot study of a home-based aerobic exercise program for sedentary cancer survivors treated with hematopoietic stem cell transplantation.

Authors: Wilson RW, Jacobsen PB, Fields KK.

Source: Bone Marrow Transplant. 2005 Feb 07

Summary:We report a pilot study of a home-based aerobic exercise program in a group of 17 adult hematopoietic stem cell transplant (HSCT) recipients. Participants had received no cancer treatment for at least 6 months and reported leisure time physical activity less than 20 min per day and fewer than three times a week during the previous month. Following baseline assessments of aerobic fitness, fatigue symptoms, and quality of life, participants were placed on home-based aerobic exercise programs consisting of 20-40 min of activity in the target heart rate zone (40-60% predicted heart rate reserve) delivered in three to five sessions per week for 12 weeks. Subjects were supplied with electronic heart rate monitors and we encouraged program adherence using weekly telephone contacts and exercise diaries. In all, 32 of the 42 qualified candidates consented (acceptance=76%). Of these, 17 kept appointments for baseline assessments, four did not complete the study (attrition=46%), and no exercise-related adverse events were reported. Scores on measures of aerobic fitness, fatigue severity, and physical well-being improved (signed ranks test; P<0.05) during program participation. Our findings suggest that individually prescribed, home-based aerobic exercise is an acceptable, safe, and potentially effective intervention for improving physical functioning and fatigue in sedentary HSCT recipients.Bone Marrow Transplantation advance online publication, 7 February 2005; doi:10.1038/sj.bmt.1704815.

Conjugated linoleic acid preserves gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma.

Authors: Graves E, Hitt A, Pariza MW, Cook ME, McCarthy DO.

Source: Res Nurs Health. 2005 Feb;28(1):48-55.

Cancer cachexia is a syndrome of weight loss, muscle wasting, fatigue, and anorexia that occurs in patients with advanced or recurrent solid tumor disease. Tumor necrosis factor-alpha (TNFalpha) and prostaglandin E2 (PGE2) have been implicated in the biology of cachexia and serve as possible targets for treatment of this condition. Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid that alters the synthesis of PGE2 and reduces the negative effects of TNF on body weight of healthy mice. We hypothesized that a diet supplemented with .5% CLA might reduce muscle wasting in mice bearing the colon-26 adenocarcinoma, an animal model of cancer cachexia. CLA preserved gastrocnemius muscle mass and reduced TNF receptors in muscle of tumor-bearing mice. These data suggest that CLA may preserve muscle mass by reducing the catabolic effects of TNF on skeletal muscle. (c) 2004 Wiley Periodicals, Inc. Res Nurs Health 28:48-55, 2005.

Comparison between daidzein and genistein antioxidant activity in primary and cancer lymphocytes.

Authors: Foti P, Erba D, Riso P, Spadafranca A, Criscuoli F, Testolin G.

Source: Arch Biochem Biophys. 2005 Jan 15;433(2):421-7.

The main objective of this study was to compare the protective effect of daidzein and genistein against induced oxidative damage in Jurkat T-cell line and in peripheral blood lymphocytes of healthy subjects. After supplementation of cells with isoflavones (from 2.5 to 20mumol/L in Jurkat T-cell and from 0.01 to 2.5mumol/L in primary lymphocytes, 24h), we determined DNA damage induced by hydrogen peroxide using the comet assay and lipid peroxidation evaluating malondialdehyde (MDA) production after ferrous ion treatment. Supplementation of Jurkat cells and primary lymphocytes with both isoflavones significantly increased DNA protection from oxidative damage at concentrations between 0.1 and 5mumol/L (P<0.05), and with just daidzein, at concentrations higher than 2.5mumol/L, there was a decrease in the production of MDA (P<0.05). Our results seem to support that daidzein is just as effective as genistein in protecting cells against oxidative damage especially with respect to DNA. Moreover, since the protective effect was found at concentrations reachable in plasma after soy consumption (less than 2mumol/L), it can be assumed that the antioxidant activity of isoflavones could really contribute to the healthy properties of soy.

The novel targets for anti-angiogenesis of genistein on human cancer cells.

Authors: Su SJ, Yeh TM, Chuang WJ, Ho CL, Chang KL, Cheng HL, Liu HS, Cheng HL, Hsu PY, Chow NH.

Source: Biochem Pharmacol. 2005 Jan 15;69(2):307-18. Epub 2004 Nov 19.

Genistein has been reported to be a natural chemopreventive in several types of human cancer. In our prior study, soy isoflavones were shown to induce cell cycle arrest and apoptosis of bladder cancer cells in the range of human urine excretion. This study was designed to identify the novel molecular basis underlying anti-angiogenic activities of soy isoflavones. An immortalized E6 and five human bladder cancer cell lines were studied by immunoassay, flow cytometry, functional activity, reverse transcription-polymerase chain reaction, immunoblotting, and transwell co-culture in vitro. The efficacy of soy isoflavones on angiogenesis inhibition in vivo was examined by nude mice xenograft and chick chorioallantoic membrane bioassay. Factors analyzed included angiogenic factors, matrix-degrading enzymes, and angiogenesis inhibitors. Genistein was the most potent inhibitor of angiogenesis in vitro and in vivo among the isoflavone compounds tested. It may also account for most of the reduced microvessel density of xenografts observed and the suppressed endothelial migration by soy isoflavones. Genistein exhibited a dose-dependent inhibition of expression/excretion of vascular endothelial growth factor(165), platelet-derived growth factor, tissue factor, urokinase plasminogen activator, and matrix metalloprotease-2 and 9, respectively. On the other hand, there was an up-regulation of angiogenesis inhibitors-plasminogen activator inhibitor-1, endostatin, angiostatin, and thrombospondin-1. In addition, a differential inhibitory effect between immortalized uroepithelial cells and most cancer cell lines was also observed. Altogether, we discovered that tissue factor, endostatin, and angiostatin are novel molecular targets of genistein. The current investigation provides further evidence in support of soy-based foods as natural dietary inhibitors of tumor angiogenesis.

Diet quality and subsequent cancer incidence and mortality in a prospective cohort of women.

Authors: Mai V, Kant AK, Flood A, Lacey JV Jr, Schairer C, Schatzkin A.

Source: Int J Epidemiol. 2005 Jan 13

BACKGROUND: We have previously reported on the utility of the Recommended Foods Score (RFS), a measure of overall diet quality, in detecting associations between diet and mortality in a cohort of older women. Using additional follow-up, we have now extended our analysis to detailed studies of associations between RFS and the mortality and incidence from common cancers.

METHODS: The RFS, the sum of 23 recommended food items consumed at least weekly, was computed from a 62-item food frequency questionnaire completed at baseline by 42 254 women with a mean age of 61 years. Multivariate adjusted relative risk (RR) of cancer mortality and incidence of the cancers for which we were able to obtain data in relation to quartiles of RFS were examined using proportional hazards regression analyses after a median follow-up period of 9.5 years.

RESULTS: We observed that RFS was inversely associated with total mortality (RR = 0.8; P < 0.001) cancer mortality (RR = 0.74; P < 0.001) as well as mortality from cancers of the breast (RR = 0.75; P < 0.06), colon/rectum (RR = 0.49; P < 0.01) and lung (RR = 0.54; P < 0.001). The risk of incident lung cancer (RR = 0.62; P < 0.001) was reduced in women in the highest vs the lowest quartile of RFS; for incident cancers of the breast, colorectum, endometrium, ovaries, and bladder, there was no RFS association. CONCLUSION: A dietary pattern reflecting a higher RFS was associated with decreased overall mortality in women, specifically cancers of the lung, colon/rectum, and to a lesser extent breast. Incidence was only decreased for lung cancers. These observations are consistent with the hypothesis that a high RFS dietary pattern, or associated lifestyle factors, might affect cancer progression and survival.

Antitumour activity of cordycepin in mice.

Authors: Yoshikawa N, Nakamura K, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M.

Source: Clin Exp Pharmacol Physiol. 2004 Dec;31 Suppl 2:S51-3.

SUMMARY 1. The antitumour effect of orally administered cordycepin, a component isolated from water extracts of Cordyceps sinensis, was examined in mice inoculated with B16 melanoma (B16-BL6) cells. 2. B16-BL6 (1 x 10(6)) cells were inoculated subcutaneously into the right footpad of mice. At 2 weeks after the cell inoculation, the enlarged primary tumour lump was weighed. Cordycepin (0, 5 and 15 mg/kg per day) was administered orally to the mice for 2 weeks from the date of tumour inoculation. Cordycepin (15 mg/kg per day) significantly reduced by 36% the wet weight of the primary tumour lump compared to that of the untreated control mice, without any loss of bodyweight or systemic toxicity. 3. Cordycepin (15 mg/kg per day) administered orally for 2 weeks inhibited the tumour enlargement in the right thigh inoculated with B16-BL6 cells premixed with extracellular matrix (Matrigel). 4. These results indicate that orally administered cordycepin inhibits melanoma cell growth in mice with no adverse effects.

Tai Chi Chuan, health-related quality of life and self-esteem: a randomized trial with breast cancer survivors.

Authors: Mustian KM, Katula JA, Gill DL, Roscoe JA, Lang D, Murphy K.

Source: Support Care Cancer. 2004 Dec;12(12):871-6. Epub 2004 Sep 30.

GOALS: Health-related quality of life (HRQL) and self-esteem are often diminished among women diagnosed and treated for breast cancer. Tai Chi is a moderate form of exercise that may be an effective therapy for improving HRQL and self-esteem among these women. We sought to compare the efficacy of Tai Chi Chuan (TCC) and psychosocial support (PST) for improving HRQL and self-esteem among breast cancer survivors.

PATIENTS AND METHODS: A group of 21 women diagnosed with breast cancer, who had completed treatment within the last 30 months were randomized to receive 12 weeks of TCC or PST. Participants in both groups met three times a week for 60 minutes. HRQL and self-esteem were assessed at baseline, 6 weeks, and 12 weeks.

RESULTS: The TCC group demonstrated significant improvements in HRQL, while the PST group reported declines in HRQL, with the differences between the two groups approaching significance at week 12. Additionally, the TCC group exhibited improvements in self-esteem, while the PST group reported declines in self-esteem, with the differences between groups reaching statistical significance at week 12. These findings, coupled with a visual inspection of the raw change scores, support the plausibility of a dose-response relationship concerning Tai Chi.

CONCLUSIONS: In this pilot investigation, the TCC group exhibited improvements in HRQL and self-esteem from baseline to 6 and 12 weeks, while the support group exhibited declines. Randomized, controlled clinical trials with larger sample sizes are needed.

Ganoderma lucidum extracts inhibit growth and induce actin polymerization in bladder cancer cells in vitro.

Authors: Lu QY, Jin YS, Zhang Q, Zhang Z, Heber D, Go VL, Li FP, Rao JY.

Source: Cancer Lett. 2004 Dec 8;216(1):9-20.

This study was conducted to investigate chemopreventive effects of Ganoderma lucidum using a unique in vitro human urothelial cell (HUC) model consisted of HUC-PC cells and MTC-11 cells. Ethanol and water extracts of fruiting bodies and spores of the G. lucidum were used to examine growth inhibition, actin polymerization status, and impact of actin remodeling on cell migration and adhesion. Results showed that ethanol extracts had a stronger growth inhibition effect than water extracts. Cell cycle analysis showed that the growth inhibition effect was associated with G2/M arrest. At non-cytotoxic concentrations (40-80 microg/ml), these extracts induced actin polymerization, which in turn inhibited carcinogen 4-aminobiphenyl induced migration in both cell lines. The increased actin polymerization was associated with increased stress fibers and focal adhesion complex formation, however, expression of matrix metalloproteinase-2 and focal adhesion kinase (total and phospholated) were unchanged, which suggests that other mechanisms may be involved.

Dietary antioxidants and human cancer.

Authors: Borek C.

Source: Integr Cancer Ther. 2004 Dec;3(4):333-41.

Epidemiological studies show that a high intake of anti-oxidant-rich foods is inversely related to cancer risk. While animal and cell cultures confirm the anticancer effects of antioxidants, intervention trials to determine their ability to reduce cancer risk have been inconclusive, although selenium and vitamin E reduced the risk of some forms of cancer, including prostate and colon cancer, and carotenoids have been shown to help reduce breast cancer risk. Cancer treatment by radiation and anticancer drugs reduces inherent antioxidants and induces oxidative stress, which increases with disease progression. Vitamins E and C have been shown to ameliorate adverse side effects associated with free radical damage to normal cells in cancer therapy, such as mucositis and fibrosis, and to reduce the recurrence of breast cancer. While clinical studies on the effect of anti-oxidants in modulating cancer treatment are limited in number and size, experimental studies show that antioxidant vitamins and some phytochemicals selectively induce apoptosis in cancer cells but not in normal cells and prevent angiogenesis and metastatic spread, suggesting a potential role for antioxidants as adjuvants in cancer therapy.

Induction of HL-60 apoptosis by ethyl acetate extract of Cordyceps sinensis fungal mycelium.

Authors: Zhang Q, Wu J, Hu Z, Li D.

Source: Life Sci. 2004 Oct 29;75(24):2911-9.

The cultivated mycelium of a Cordyceps sinensis (Cs) fungus was sequentially extracted by petroleum ether, ethyl acetate (EtOAc), ethanol and water. The EtOAc extract showed the most potent cytotoxic effect against the proliferation of human premyelocytic leukemia cell HL-60, with an ED(50) <!--= 25 microg/ml for 2-day treatment. The EtOAc extract induced the characteristic apoptotic symptoms in the HL-60 cells, DNA fragmentation and chromatin condensation, occurring within 6-8 h of treatment at a dose of 200 microg/ml. The activation of caspase-3 and the specific proteolytic cleavage of poly ADP-ribose polymerase were detected during the course of apoptosis induction. These results suggest that the Cs mycelium extract inhibited the cancer cell proliferation by inducing cell apoptosis.

Zinc deficiency, DNA damage and cancer risk.

Authors: J Nutr Biochem. 2004 Oct;15(10):572-8.

Source: J Nutr Biochem. 2004 Oct;15(10):572-8.

A large body of evidence suggests that a significant percentage of deaths resulting from cancer in the United States could be avoided through greater attention to proper and adequate nutrition. Although many dietary compounds have been suggested to contribute to the prevention of cancer, there is strong evidence to support the fact that zinc, a key constituent or cofactor of over 300 mammalian proteins, may be of particular importance in host defense against the initiation and progression of cancer. Remarkably, 10% of the U.S. population consumes less than half the recommended dietary allowance for zinc and are at increased risk for zinc deficiency. Zinc is known to be an essential component of DNA-binding proteins with zinc fingers, as well as copper/zinc superoxide dismutase and several proteins involved in DNA repair. Thus, zinc plays an important role in transcription factor function, antioxidant defense and DNA repair. Dietary deficiencies in zinc can contribute to single- and double-strand DNA breaks and oxidative modifications to DNA that increase risk for cancer development. This review will focus on potential mechanisms by which zinc deficiency impairs host protective mechanisms designed to protect against DNA damage, enhances susceptibility to DNA-damaging agents and ultimately increases risk for cancer.

Mediterranean diet and cancer.

Authors: La Vecchia C.

Source: Public Health Nutr. 2004 Oct;7(7):965-8.

OBJECTIVE: To analyse the role of various aspects of the Mediterranean diet in several common epithelial cancers, including digestive and selected non-digestive tract neoplasms.

DESIGN: Systematic analysis of data from a series of case-control studies.

SETTING: Northern Italy, between 1983 and 1998.

SUBJECTS: Over 12,000 cases of 20 cancer sites and 10,000 controls.

RESULTS: For most epithelial cancers, the risk decreased with increasing vegetable and fruit consumption, with relative risk (RR) between 0.3 and 0.7 for the highest versus the lowest tertile. For digestive tract cancers, population-attributable risks for low intake of vegetables and fruit ranged between 15 and 40%. A protective effect was observed also for breast, female genital tract, urinary tract and a few other epithelial neoplasms. A number of antioxidants and other micronutrients showed an inverse relationship with cancer risk, but the main components responsible for the favourable effect of a diet rich in vegetables and fruit remain undefined. Fish tended to be another favourable diet indicator. In contrast, subjects reporting frequent red meat intake showed RRs above unity for several common neoplasms. Intake of whole-grain foods was related to a reduced risk of several types of cancer, particularly of the upper digestive tract. This may be due to a favourable role of fibre, but the issue is still open to discussion. In contrast, refined grain intake and, consequently, glycaemic load and glycaemic index were associated with increased risk of different types of cancer including, among others, breast and colorectal.

CONCLUSIONS: A low-risk diet for cancer in the Mediterranean would imply increasing the consumption of fruit and vegetables, as well as avoiding increasing the intakes of meat and refined carbohydrates. Further, olive oil and other unsaturated fats, which are also typical aspects of the Mediterranean diet, should be preferred to saturated ones.

Intake of whole grains and vegetables determines the plasma enterolactone concentration of danish women.

Authors: Johnsen NF, Hausner H, Olsen A, Tetens I, Christensen J, Knudsen KE, Overvad K, Tjonneland A.

Source: J Nutr. 2004 Oct;134(10):2691-7.

The mammalian lignan enterolactone (ENL), which is produced from dietary plant-lignan precursors by the intestinal microflora, may protect against breast cancer and other hormone-dependent cancers. This cross-sectional study examined which variables related to diet and lifestyle were associated with high plasma concentrations of ENL in Danish postmenopausal women. Plasma ENL was measured by time-resolved fluoroimmunoassay in 857 Danish women aged 50-64 y who participated in a prospective cohort study. Diet was assessed using a semiquantitative FFQ, and background information on lifestyle was collected using a self-administered questionnaire. Multiple analyses of covariance were completed in two steps. The median plasma ENL concentration was 27 nmol/L (range 0-455 nmol/L). In covariance analyses, positive associations were found between consumption of cereals, vegetables, and beverages and plasma ENL concentration. When analyzing subgroups of these food groups, the associations were confined to whole-grain products, cabbage, leafy vegetables, and coffee. For fat and the nondietary variables, negative associations between BMI, smoking, and frequency of bowel movements and plasma ENL concentration were observed. These data show that foods high in ENL precursors are associated with high concentrations of ENL. Furthermore, smoking, frequent bowel movements, and consumption of fat seems to have a negative affect on the ENL concentration. In conclusion, whole grains and vegetables are the most important dietary providers of plant lignans for the concentration of ENL in Danish postmenopausal women, and if ENL is found to protect against cancer or heart disease, the intake of whole grains and vegetables should be increased.

Selenium prevents tumor development in a rat model for chemical carcinogenesis.

Authors: Bjorkhem-Bergman L, Torndal UB, Eken S, Nystrom C, Capitanio A, Larsen EH, Bjornstedt M, Eriksson LC.

Source: Carcinogenesis. 2004 Sep 30

Previous studies in animals and humans have shown that selenium compounds can prevent cancer development. In this work we studied the tumor preventive effect of selenium supplementation, administrated as selenite, in the initiation, promotion and progression phases in a synchronised rat model for chemically induced hepatocarcinogenesis, the resistant hepatocyte model. Selenite in supra-nutritional but subtoxic doses (1 and 5 ppm) was administrated to the animals through the drinking water. Such supplementation during the initiation phase did not have tumor preventive effect. However, selenite treatment during the promotion phase decreased the volume fraction of preneoplastic liver nodules from 38% in control animals to 25% (1 ppm) and 14% (5 ppm) in the selenite-supplemented groups. In addition the cell proliferation within the nodules decreased from 42% in control to 22% (1 ppm) and 17% (5 ppm). Immunohistochemical staining for the selenoenzyme thioredoxin reductase 1 (TrxR1) revealed an increased expression of the enzyme in liver nodules compared to the surrounding tissue. The activity was reduced to 50% in liver homogenates from selenium treated animals but the activity of the selenoenzyme glutathione peroxidase was essentially unaltered. Selenite treatment (5 ppm) during the progression phase resulted in significantly lower volume fraction of liver tumors (14% compared to 26 %) along with a decrease of cell proliferation within the tumors (34 % compared to 63 %). Taken together our data indicate that the carcinogenetic process may be prevented by selenium supplementation both during the promotion and the progression phase.

Immunomodulating and anti-tumor action of extracts of several mushrooms.

Authors: Shamtsyan M, Konusova V, Maksimova Y, Goloshchev A, Panchenko A, Simbirtsev A, Petrishchev N, Denisova N.

Source: J Biotechnol. 2004 Sep 30;113(1-3):77-83.

Aqueous extracts from fruit bodies and mycelia of various higher Basidiomycetes were studied in search for reliable biological effects. In vitro and in vivo experiments were conducted. The results showed that the aqueous extracts demonstrated various types of marked biological actions: an increased production of reactive oxygen forms by neutrophil cells of human peripheral blood; a significant mitogenic activity in a wide range of concentrations; stimulation on production of inflammatory cytokines interleukine 1-beta and interleukine-8 by peripheral blood cells; a decrease in both average tumor size in mice with transplanted melanoma B16 and a manifestation of tumorous intoxication; and a prolongation in the survival rate of such mice.

Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections; Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy.

Authors: Dijsselbloem N, Vanden Berghe W, De Naeyer A, Haegeman G.

Source: Biochem Pharmacol. 2004 Sep 15;68(6):1171-85.

Interleukin-6 is a pleiotropic cytokine which plays a crucial role in immune physiology and is tightly controlled by hormonal feedback mechanisms. After menopause or andropause, loss of the normally inhibiting sex steroids (estrogen, testosterone) results in elevated IL6 levels that are further progressively increasing with age. Interestingly, excessive IL6 production promotes tumorigenesis (breast, prostate, lung, colon, ovarian), and accounts for several disease-associated pathologies and phenotypical changes of advanced age, such as osteoporosis, rheumatoid arthritis, multiple myeloma, neurodegenerative diseases and frailty. In this respect, pharmacological modulation of IL6 gene expression levels may have therapeutical benefit in preventing cancer progression, ageing discomforts and restoring immune homeostasis. Although "plant extracts" are used in folk medicine within living memory, it is only since the 20th century that numerous scientific investigations have been performed to discover potential health-protective food compounds or "nutraceuticals" which might prevent cancer and ageing diseases. About 2000 years ago, Hippocrates already highlighted "Let food be your medicine and medicine be your food". Various nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient or excessive intakes can have negative consequences on the organism's immune status and susceptibility to a variety of pathologies. Over the last few decades, various immune-modulating nutrients have been identified, which interfere with IL6 gene expression. Currently, a broad range of phyto-pharmaceuticals with a claimed hormonal activity, called "phyto-estrogens", is recommended for prevention of various diseases related to a disturbed hormonal balance (i.e. menopausal ailments and/or prostate/breast cancer). In this respect, there is a renewed interest in soy isoflavones (genistein, daidzein, biochanin) as potential superior alternatives to the synthetic selective estrogen receptor modulators (SERMs), which are currently applied in hormone replacement therapy (HRT). As phyto-chemicals integrate hormonal ligand activities and interference with signaling cascades, therapeutic use may not be restricted to hormonal ailments only, but may have applications in cancer chemoprevention and/or NF-kappaB-related inflammatory disorders as well.

Transforming the nature of fatigue through exercise: qualitative findings from a multidimensional exercise programme in cancer patients undergoing chemotherapy.

Authors: Adamsen L, Midtgaard J, Andersen C, Quist M, Moeller T, Roerth M.

Source: Eur J Cancer Care (Engl). 2004 Sep;13(4):362-70.

ADAMSEN L., MIDTGAARD J., ROERTH M., ANDERSEN C., QUIST M. & MOELLER T. (2004) European Journal of Cancer Care13, 362-370 Transforming the nature of fatigue through exercise: qualitative findings from a multidimensional exercise programme in cancer patients undergoing chemotherapy The objective of this study was to explore the nature of fatigue in cancer patients with advanced stages of disease undergoing chemotherapy and concurrently participating in a 6-week multidimensional exercise programme (physical exercise, relaxation, massage and body-awareness training). Semi-structured qualitative interviews were conducted with 23 patients between 18 and 65 years of age prior to, during, and at termination of the programme. The findings endorsed that physical debilitation, fatigue, and uncertainty of physical capacity were the patients' motivation for participation. Throughout the programme the patients experienced exercise-induced fatigue, which they associated with a sense of increased physical strength, improvement in energy and physical well-being. This positive sense of fatigue can be seen as a contrast to the negative chemotherapy-induced fatigue, which is characterized by physical discomfort and uncontrollable exhaustion. The patients learned to manoeuvre through periods of intense fatigue by using exercise as a strategy to adjust their sense of physical debilitation. Visibility of fatigue's qualitative aspects is necessary if patients are to be encouraged to stay active and to set realistic goals. The transformation process of fatigue identified in this study supports the theory of exercise as a beneficial intervention strategy in the treatment of cancer-related fatigue.

Isolation of an anti-angiogenic substance from Agaricus blazei Murill: Its antitumor and antimetastatic actions.

Authors: Kimura Y, Kido T, Takaku T, Sumiyoshi M, Baba K.

Source: Cancer Sci. 2004 Sep;95(9):758-64.

We previously found that ergosterol isolated from Agaricus blazei inhibited tumor growth through the inhibition of tumor-induced neovascularization. In the present study, we isolated further anti-angiogenic substances (A-1 and A-2) from this fungus using an assay system of angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor, and A-1 was identified as sodium pyroglutamate. Next, we examined the antitumor and antimetastatic actions of A-1 using Lewis lung carcinoma (LLC)-bearing mice. A-1 (30, 100 and 300 mg/kg) inhibited tumor growth and metastasis to the lung. The reduction of the numbers of splenic lymphocytes, CD4(+) and CD8(+) T cells in LLC-bearing mice was inhibited by the oral administration of A-1 (30, 100 and 300 mg/kg). Further, A-1 increased the number of apoptotic cells of tumors and the numbers of CD8(+) T and natural killer cells invading the tumors, and inhibited the increase of von Willebrand factor expression (a measure of angiogenesis) in the tumors. These results suggest that the antitumor and antimetastatic actions of A-1 (sodium pyroglutamate) may be associated with inhibition of the reduction of immune response caused by the tumor growth and tumor-induced neovascularization. This is the first report showing that sodium pyroglutamate isolated from A. blazei as an anti-angiogenic substance has potent antitumor and antimetastatic actions, as well as immune-modulatory activity, in tumor-bearing mice.

An overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines.

Authors: Maggiora M, Bologna M, Ceru MP, Possati L, Angelucci A, Cimini A, Miglietta A, Bozzo F, Margiotta C, Muzio G, Canuto RA.

Source: Int J Cancer. 2004 Aug 12;:NA. [Epub ahead of print]

Both n-6 and n-3 polyunsaturated fatty acids are dietary fats important for cell function, being involved in several physiologic and pathologic processes, such as tumorigenesis. Linoleic acid and conjugated linoleic acid, its geometrical and positional stereoisomer, were tested on several human tumor cell lines originating from different tissues and with different degrees of malignancy. This was to provide the widest possible view of the impact of dietary lipids on tumor development. While linoleic acid exerted different effects, ranging from inhibitory to neutral, even promoting growth, conjugated linoleic acid inhibited growth in all lines tested and was particularly effective against the more malignant cells, with the exception of mammary tumor cells, in which behavior was the opposite, the more malignant cell line being less affected. The inhibitory effect of conjugated linoleic acid on growth may be accompanied by different contributions from apoptosis and necrosis. The effects of conjugated linoleic acid on growth or death involved positive or negative variations in PPARs. The important observation is that a big increase of PPARalpha protein occurred in cells undergoing strong induction of apoptosis, whereas PPARbeta/delta protein decreased. Although PPARalpha and PPARbeta/delta seem to be correlated to execution of the apoptotic program, the modulation of PPARgamma appears to depend on the type of tumor cell, increasing as protein content, when inhibition of cell proliferation occurred. In conclusion, CLA may be regarded as a component of the diet that exerts antineoplastic activity and its effect may be antiproliferative or pro-apoptotic. Copyright 2004 Wiley-Liss, Inc.

Antitumor activity of beta-D-glucan from Libyan dates.

Authors: Ishurd O, Zgheel F, Kermagi A, Flefla M, Elmabruk M.

Source: J Med Food. 2004 Summer;7(2):252-5.

Beta-glucan with antitumor activities was isolated from Libyan dates, and the structure of the purified glucan was characterized using methods such as methylation, periodate oxidation, and acetolysis. Glucans were found to exhibit potent antitumor activity; this activity could be correlated to their (1-->3)-beta-D-glucan linkages. Such antitumor glucans have also been obtained from a number of other sources, such as yeast, fungi, bacteria, and plants. This is the first study to report antitumor activity for date glucan.

Medicinal mushroom extracts inhibit ras-induced cell transformation and the inhibitory effect requires the presence of normal cells.

Authors: Hsiao WL, Li YQ, Lee TL, Li N, You MM, Chang ST.

Source: Carcinogenesis. 2004 Jul;25(7):1177-83.

Previously, we developed a simple Rat 6 (R6) cell system by which the inhibitory effects of non-cytotoxic chemicals can be assessed by focus formation assay upon transfection of ras oncogene to the host cells. Using this system, two well studied medicinal mushrooms Ganoderma lucidum and Tricholoma lobayense with anticancer potential were examined for their possible advert effects on cell transformation induced by ras oncogene. Results indicated that both species of mushrooms yielded strong inhibitory effects on ras-induced cell transformation. Further study on T.lobayense indicated that the DEAE-column-bound, polysaccharides (PS)-peptide enriched, but not the unbound fraction, showed strong inhibition in a dosage-dependent manner. Subsequent time course study revealed that the continued presence of the extract in the transfected cultures was required for a maximum inhibitory effect. At the same time, we also observed that significant levels of inhibition occurred even when the application of the extract was delayed until day 12 after transfection. Using a stable transformed cell line, R6/GFP-Ras expressing green fluorescent protein-ras fusion protein in a co-culture assay with normal R6 cells, we demonstrated that R6/GFP-Ras cells grew into green fluorescent foci with striking transforming morphology in the absence of extracts. However, in the presence of extracts, R6/GFP-Ras cells, in most cases, remained as small colonies compiled with only a few green fluorescent cells. Moreover, the inhibitory effect requires the presence of R6 cells. In our study, mushroom extracts have no effect on the growth of individually cultured normal and transformed R6 cells. It is noteworthy that the extracts do not affect the level, or the subcellular localization of the Ras protein. Collectively, the data strongly suggest that the inhibitory effect of the mushroom extracts is not due to a direct killing of the transformed cells, rather, it may be mediated through the surrounding normal R6. While the general understanding of the antitumor effect of PS and PSPC is mediated through the cytokines released by activated macrophages and T-lymphocytes, our data may provide a novel alternative mechanism that the mushroom PS peptides may exert anticancer effect by targeting the ras-mediated signaling pathway.

Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models.

Authors: Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostroff GR, Xing PX, Cheung NK, Ross GD.

Source: J Immunol. 2004 Jul 15;173(2):797-806.

Antitumor mAb bind to tumors and activate complement, coating tumors with iC3b. Intravenously administered yeast beta-1,3;1,6-glucan functions as an adjuvant for antitumor mAb by priming the inactivated C3b (iC3b) receptors (CR3; CD11b/CD18) of circulating granulocytes, enabling CR3 to trigger cytotoxicity of iC3b-coated tumors. Recent data indicated that barley beta-1,3;1,4-glucan given orally similarly potentiated the activity of antitumor mAb, leading to enhanced tumor regression and survival. This investigation showed that orally administered yeast beta-1,3;1,6-glucan functioned similarly to barley beta-1,3;1,4-glucan with antitumor mAb. With both oral beta-1,3-glucans, a requirement for iC3b on tumors and CR3 on granulocytes was confirmed by demonstrating therapeutic failures in mice deficient in C3 or CR3. Barley and yeast beta-1,3-glucan were labeled with fluorescein to track their oral uptake and processing in vivo. Orally administered beta-1,3-glucans were taken up by macrophages that transported them to spleen, lymph nodes, and bone marrow. Within the bone marrow, the macrophages degraded the large beta-1,3-glucans into smaller soluble beta-1,3-glucan fragments that were taken up by the CR3 of marginated granulocytes. These granulocytes with CR3-bound beta-1,3-glucan-fluorescein were shown to kill iC3b-opsonized tumor cells following their recruitment to a site of complement activation resembling a tumor coated with mAb.

New approaches to the role of diet in the prevention of cancers of the alimentary tract.

Authors: Johnson IT.

Source: Mutat Res. 2004 Jul 13;551(1-2):9-28.

Cancers of the alimentary tract are, collectively, amongst the major causes of morbidity and deaths from cancer across the world today. Of the 10 million new cases of cancer diagnosed in 2000, about 2.3 million were cancers of the pharynx, oesophagus, stomach or colorectum. Nevertheless, epidemiological studies indicate that cancers of the digestive organs are also amongst the most susceptible to modification by dietary factors. International variations in incidence suggest that round three quarters of all sporadic colorectal cancers are attributable to diet. Even within the relatively uniform environment of the European Union, there are variations in the incidence of colorectal and oesophageal cancers of about two- and six-fold, respectively. Carcinomas of the alimentary tract arise from epithelial cells via distinct sequences of neoplastic change, which require a large fraction of an individual's lifespan. The best characterised of these is the adenoma-carcinoma sequence of colorectal carcinogenesis, in which progressive loss of differentiation and normal morphology in a growing lesion is associated with the acquisition of somatic mutations, and of aberrant methylation of CpG-islands, leading to gene silencing. These molecular events are accompanied by functional changes, including increased mitosis and evasion of apoptosis. There is little evidence that diet exerts its effects primarily through food-borne carcinogens that can be identified and eliminated from the food-chain. It is far more probable that the adverse effects of diet are caused largely by over-consumption of energy, coupled with inadequate intakes of protective substances, including micronutrients, dietary fibre and a variety of phytochemicals. The latter are biologically active secondary plant metabolites, many of which modify cell proliferation and induce apoptosis in vitro. There is growing evidence that such effects also occur in vivo, and that they can suppress the progress of neoplasia. Carcinomas of the oesophagus, stomach and colon all appear to be partially preventable by diets rich in fruits and vegetables. Plant foods contain a variety of components including micronutrients, polyunsaturated fatty acids, and secondary metabolites such as glucosinolates and flavonoids, many of which can inhibit cell proliferation and induce apoptosis, and which may well act synergistically when combined in the human diet. The future challenge is to fully characterise and evaluate these effects at the cellular and molecular level, so at to exploit their full potential as protective mechanisms for the population as a whole.

Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients.

Authors: Heller AR, Rossel T, Gottschlich B, Tiebel O, Menschikowski M, Litz RJ, Zimmermann T, Koch T.

Source: Int J Cancer. 2004 Sep 10;111(4):611-6.

Epidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Omega-3 PUFAs in fish oil (FO) can inhibit the growth of human cancer cells in vitro and in vivo. These effects are related to the uptake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the cellular substrate pool and their competitive metabolism with arachidonic acid (AA) at the cyclooxygenase and 5-lipoxygenase levels. The metabolites of EPA and DHA have less inflammatory and immunosuppressant potency than the substances derived from AA. Based on previous experimental data, we hypothesized that FO supplementation after major abdominal cancer surgery would improve hepatic and pancreatic function. Ours was a prospective, randomized, double-blinded clinical trial on 44 patients undergoing elective major abdominal surgery, randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO 1.0 g/kg body weight daily, n = 20) for 5 days or a combination of FO and SO (FO 0.2 + SO 0.8 g/kg body weight daily, n = 24). Compared to pure SO supplementation in the postoperative period, FO significantly reduced ASAT [0.8 +/- 0.1 vs. 0.5 +/- 0.1 mmol/(l. sec)], ALAT [0.9 +/- 0.1 vs. 0.6 +/- 0.1 mmol/(l. sec)], bilirubin (16.1 +/- 5.3 vs. 6.9 +/- 0.6 mmol/l), LDH (7.7 +/- 0.4 vs. 6.7 +/- 0.4 mmol/(l. sec) and lipase (0.6 +/- 0.1 vs. 0.4 +/- 0.1 micromol/(l. sec) in the postoperative course. Moreover, patients with increased risk of sepsis (IL-6/IL-10 ratio >8) showed a tendency to shorter ICU stay (18 hr) under omega-3 PUFA treatment. Weight loss as encountered after the SO emulsion of 1.1 +/- 2.2 kg was absent in the FO group. After major abdominal tumor surgery, FO supplementation improved liver and pancreas function, which might have contributed to the faster recovery of patients. Copyright 2004 Wiley-Liss, Inc.

Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis.

Authors: Lau CB, Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, Chan HH, Chow MS.

Source: Life Sci. 2004 Jul 2;75(7):797-808.

Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used Chinese medicinal herbs. Although recent studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the objective of this study was to examine the in vitro cytotoxic activities of a standardized aqueous ethanol extract prepared from Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. Cell death ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis. The present results demonstrated that CV extract at 50 to 800 microg/ml dose-dependently suppressed the proliferation of Raji, NB-4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC(50) values: HL-60 (147.3 +/- 15.2 microg/ml), Raji (253.8 +/- 60.7 microg/ml) and NB-4 (269.3 +/- 12.4 microg/ml). The extract however did not exert any significant cytotoxic effect on normal liver cell line WRL (IC(50) > 800 microg/ml) when compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon the treatment of CV extract, while no significant nucleosome production was detected in extract-treated WRL cells. The CV extract was found to selectively and dose-dependently inhibit the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway.

Apoptosis of human primary gastric carcinoma cells induced by genistein.

Authors: Zhou HB, Chen JJ, Wang WX, Cai JT, Du Q.

Source: World J Gastroenterol. 2004 Jun 15;10(12):1822-5.

AIM: To investigate the apoptosis in primary gastric cancer cells induced by genistein, and the relationship between this apoptosis and expression of bcl-2 and bax.

METHODS: MTT assay was used to determine the cell growth inhibitory rate in vitro. Transmission electron microscope and TUNEL staining were used to quantitatively and qualitatively detect the apoptosis of primary gastric cancer cells before and after genistein treatment. Immunohistochemical staining and RT-PCR were used to detect the expression of apoptosis-associated genes bcl-2 and bax.

RESULTS: Genistein inhibited the growth of primary gastric cancer cells in dose-and time-dependent manner. Genistein induced primary gastric cancer cells to undergo apoptosis with typically apoptotic characteristics. TUNEL assay showed that after the treatment of primary gastric cancer cells with genistein for 24 to 96 h, the apoptotic rates of primary gastric cancer cells increased time-dependently. Immunohistochemical staining showed that after the treatment of primary gastric cancer cells with genistein for 24 to 96 h, the positivity rates of Bcl-2 proteins were apparently reduced with time and the positivity rates of Bax proteins were apparently increased with time. After exposed to genistein at 20 micromol/L for 24, 48, 72 and 96 respectively, the density of bcl-2 mRNA decreased progressively and the density of bax mRNA increased progressively with elongation of time.

CONCLUSION: Genistein is able to induce the apoptosis in primary gastric cancer cells. This apoptosis may be mediated by down-regulating the apoptosis- associated bcl-2 gene and up-regulating the expression of apoptosis-associated bax gene.

Dietary sources of vitamin C, vitamin E and specific carotenoids in Spain.

Authors: Garcia-Closas R, Berenguer A, Jose Tormo M, Jose Sanchez M, Quiros JR, Navarro C, Arnaud R, Dorronsoro M, Dolores Chirlaque M, Barricarte A, Ardanaz E, Amiano P, Martinez C, Agudo A, Gonzalez CA.

Source: Br J Nutr. 2004 Jun;91(6):1005-11.

A cross-sectional study was conducted within the Spanish cohort of the European Prospective Investigation in Cancer and Nutrition to assess the principal food sources of vitamin C, vitamin E, alpha-carotene, beta-carotene, lycopene, lutein, beta-cryptoxanthin and zeaxanthin in an adult Spanish population. The study included 41 446 healthy volunteers (25 812 women and 15 634 men), aged 29-69 years, from three Spanish regions in the north (Asturias, Navarra and Guipuzcoa) and two in the south (Murcia and Granada). Usual food intake was estimated by personal interview through a computerized version of a dietary history questionnaire. Foods that provided at least two-thirds of the studied nutrients were: fruits (mainly oranges) (51 %) and fruiting vegetables (mainly tomato and sweet pepper) (20 %) for vitamin C; vegetable oils (sunflower and olive) (40 %), non-citrus fruits (10 %), and nuts and seeds (8 %) for vitamin E; root vegetables (carrots) (82 %) for alpha-carotene; green leafy (28 %), root (24 %) and fruiting vegetables (22 %) for beta-carotene; fruiting vegetables (fresh tomato) (72 %) for lycopene; green leafy vegetables (64 %) for lutein; citrus fruits (68 %) for beta-cryptoxanthin; citrus fruits (43 %) and green leafy vegetables (20 %) for zeaxanthin. In conclusion, the main food sources of nutrients with redox properties have been identified in a Mediterranean country. This could provide an insight into the interpretation of epidemiological studies investigating the role of diet in health and disease.

Conjugated linoleic acid modulation of cell membrane in leukemia cells.

Authors: Agatha G, Voigt A, Kauf E, Zintl F.

Source: Cancer Lett. 2004 Jun;209(1):87-103.

This study compared the cellular uptake of pure conjugated linoleic acid isomers (CLA(9c,11t) and CLA(9c,11c)) to linoleic acid (LA) and their effects on polyunsaturated fatty acid (PUFA) synthesis, its metabolism into conjugated long chain fatty acids (FAs) by desaturation and chain-elongation as well as cell proliferation and the associated anticarcinogenic effects on various human leukemia cell lines (K562, REH, CCRF-CEM and U937 cells). Furthermore, selective effects of this individual isomers of CLA on desaturation steps involved in the biosynthesis of PUFAs associated with cell growth were investigated. CLA isomers supplemented in the culture medium was readily incorporated and esterified into phospholipids (PLs) in the four cell lines in a concentration- and time-dependent manner. The incorporation of the specific CLA isomers in PLs was similar to LA. All four incubating leukemia cells (40 microM CLA for 48 h) showed very high cellular CLA content in PLs (range: 32-63 g FA/100 g total phospholipid fatty acid) affected by the nature of CLA and the cell type. Supplementation with CLA or LA altered also cell membrane composition by n-6 PUFA synthesis. Accordingly, CLA metabolism interferes with LA metabolism. We were able to show that CLA isomers are converted by the leukemia cells of the same metabolic pathway into conjugated diene fatty acids (CDFAs) as LA into non-conjugated PUFAs. In this view, the gas chromatography-flame ionization detector detection of major CDFAs (CD-18:3, CD-20:2 and CD-20:3) in cell membrane of CLA-treated cultures resulted from successive Delta6-desaturation, elongation and Delta5-desaturation of CLA isomers. However, in comparison to LA, relatively lower amounts of elongation and/or desaturation metabolites were detected for CLA(9c,11t), and only minor amounts or trace CDFAs were observed for CLA(9c,11c). Furthermore, CLA(9c,11t) revealed only very low levels of CD-20:4 FA and no CLA(9c,11c)-conversion could be detected. The metabolization of CLA indicated that CLA(9c,11c)

Effects of extracts from Brazilian sun-mushroom (Agaricus blazei) on the NK activity and lymphoproliferative responsiveness of Ehrlich tumor-bearing mice.

Authors: Kaneno R, Fontanari LM, Santos SA, Di Stasi LC, Rodrigues Filho E, Eira AF.

Source: Food Chem Toxicol. 2004 Jun;42(6):909-16.

Agaricus blazei Murrill, is an edible and medicinal mushroom which is popularly consumed due to its antitumoral properties. The immunomodulatory effects of methanol (METH), dichloromethane (DM) and n-hexane (HEX) extracts of this mushroom were evaluated in Ehrlich tumor-bearing mice. Subcutaneous inoculation of Ehrlich tumor cells inhibited the natural killer (NK) activity of spleen cells (specific lysis=6.18+/-2.56%) compared with normal mice (17.59+/-7.77%). Treatment of tumor-bearing mice with the extracts for 10 days restored the natural killer activity against Yac-1 target cells and the best results were observed by treatment with the HEX extract (21.48+/-5.26%). Treatment of the animals with the HEX extract for 10 days was also able to stimulate the mitogen-induced lymphoproliferative activity of spleen cells. Thirty days after the treatment, all groups presented low proliferative activity. Specific antibody production was observed to be higher in the groups treated with the DM or METH extract 30 days after the treatment. Analysis of the 3 extracts by gas chromatography mass spectrum (GCMS) and magnetic nuclear resonance (MNR) showed that the HEX extract contains mainly sugar and fatty acids and that the METH extract also contains sugar and possibly amino acids.

Indian food ingredients and cancer prevention - an experimental evaluation of anticarcinogenic effects of garlic in rat colon.

Authors: Sengupta A, Ghosh S, Bhattacharjee S, Das S.

Source: Asian Pac J Cancer Prev. 2004 Apr-Jun;5(2):126-32.

The major food items of Indian cuisine include rice, wheat, diary products, and abundant fruits and vegetables. Beside these, there are several kinds of herbs and spices as important ingredients, containing many phytochemicals with medicinal properties, adding taste to Indian cuisine. An impressive body of data exists in support of the concept that Indian food ingredients can be used in preventive strategies aimed at reducing the incidence and mortality of different types of cancers because of their antioxidative, antimutagenic and anticarcinogenic properties. Vital ingredients used in Indian cooking include turmeric, cloves, ginger, aniseed, mustard, saffron, cardamom and garlic Garlic is an indispensable ingredient of Indian food and this report concerns the chemopreventive efficacy of garlic in an azoxymethane induced rodent colon carcinogenesis model. The effect of garlic was evaluated in terms of aberrant crypt foci, putative preneoplastic lesions in the colon. In addition, cell proliferation and levels of apoptosis were determined and the expression of cyclooxygenase-2 protein was analyzed. Following treatment, significant inhibition of cell proliferation and induction of apoptosis, as well as suppression of cyclooxygenase-2 activity were observed, associated with significant reduction in the incidence of aberrant crypt foci. The study points to combined protective effects of garlic components on colon carcinogenesis.

Effects of Cordyceps militaris extract on angiogenesis and tumor growth.

Authors: Yoo HS, Shin JW, Cho JH, Son CG, Lee YW, Park SY, Cho CK.

Source: Acta Pharmacol Sin. 2004 May;25(5):657-65.

AIM: To evaluate the effects of Cordyceps militaris extract (CME) on angiogenesis and tumor growth.

METHODS: Human umbilical vein endothelial cells (HUVEC), HT1080, and B16-F10 cells were used. DNA fragment, angiogenic related gene expressions (MMPs, bFGF, VEGF, etc), capillary tube formation, wound healing in vitro, tumor growth in vivo were measured.

RESULTS: CME inhibited growth of HUVECs and HT1080 (P<0.01). CME 100 and 200 mg/L reduced MMP-2 gene expression in HT1080 cells by 6.0 % and 22.9 % after 3-h and 14.9 % and 32.8 % after 6-h treatment. CME did not affect MMP-9 gene expression in B16-F10 melanoma cells. CME 100 and 200 mg/L also reduced bFGF gene expression in HUVECs by 22.2 % and 41.3 %. CME inhibited tube formation of endothelial cells in vitro and in vivo. CME repressed the growth of B16-F10 melanoma cells in mice compared with control group (P<0.05).

CONCLUSION: CME has antiangiogenetic properties.

Dietary cancer and prevention using antimutagens.

Authors: Ferguson LR, Philpott M, Karunasinghe N.

Source: Toxicology. 2004 May 20;198(1-3):147-59.

Many of the cancers common in the Western world, including colon, prostate and breast cancers, are thought to relate to dietary habits. Of the known risk factors, many will act through increasing the probability of mutation. Recognised dietary mutagens include cooked meat compounds, N-nitroso compounds and fungal toxins, while high meat and saturated fat consumption, increasing rates of obesity, and regular consumption of alcohol and tobacco are all dietary trends that could indirectly enhance the probability of mutation. However, there are significant difficulties in implementing and sustaining major dietary changes necessary to reduce the population's intake of dietary mutagens. Dietary antimutagens may provide a means of slowing progression toward cancer, and be more acceptable to the population. Consideration of genetic mechanisms in cancer development suggest several distinct targets for intervention. Strategies that reduce mutagen uptake may be the most simple intervention, and the one least likely to result in undesirable side effects. Certain (but not all) types of dietary fibres appear to reduce mutation through this mechanism, as may certain probiotics and large planar molecules such as chlorophyllin. Antioxidants have been suggested to scavenge free radicals, and prevent their interactions with cellular DNA. Small molecule dietary antioxidants include ascorbic acid, Vitamin E, glutathione, various polyphenols and carotenoids. We found a statistically significant relationship between colon cancer incidence and soil selenium status across different regions of New Zealand. Additionally, a study of middle-aged men suggested that blood selenium levels lower than 100ng/ml were inadequate for repair or surveillance of oxidative (and other) DNA damage. We suggest that selenium will be an important antimutagen, at least in New Zealand, possibly through antioxidant effects associated with selenium's role in enzymes associated with endogenous repair of DNA damage. Modulation of xenobiotic metabolizing enzymes is well recognised as cancer-protective, and is a property of various flavonoids and a number of sulfur-containing compounds. Many fruits and vegetables contain compounds that will protect against mutation and cancer by several mechanisms. For example, kiwifruit has antioxidant effects and may also affect DNA repair enzymes. Dietary folate may be a key factor in maintenance of methylation status, while enhanced overall levels of vitamins and minerals may retard the development of genomic instability. The combination of each of these factors could provide a sustainable intervention that might usefully delay the development of cancer in New Zealand and other populations. Although there are a range of potentially antimutagenic fruits, vegetables and cereals available to these populations, current intake is generally below the level necessary to protect from dietary or endogenous mutagens. Dietary supplementation may provide an alternative approach.

Role of oxidative stress and the antioxidant network in cutaneous carcinogenesis.

Authors: Sander CS, Chang H, Hamm F, Elsner P, Thiele JJ.

Source: Int J Dermatol. 2004 May;43(5):326-35.

Abstract Melanoma and nonmelanoma skin cancers are among the most prevalent cancers in the human population. Solar ultraviolet radiation is considered a major etiological factor but the relationship between dose, timing, and nature of exposure to tumor development is still unclear. Free radicals are generated by normal physiologic processes, including aerobic metabolism and inflammatory response, but may inflict cellular damage when generation is increased and antioxidant defense mechanisms are overwhelmed. Important findings supporting the free radical hypothesis in skin carcinogenesis are: (1) Reactive oxygen species (ROS) are generated in UVA- and UVB-irradiated skin in excessive doses, (2) the natural cutaneous antioxidant defense is impaired upon UV-exposure, (3) free radicals are involved in all steps of carcinogenesis, (4) supplementation with antioxidants can inhibit skin carcinogenesis, and (5) conditions that increase ROS generation enhance photocarcinogenesis. These findings provide a promising rationale for the development of powerful new antioxidant strategies in the prevention and therapy of skin cancer.

The future of gastric cancer prevention.

Authors: Correa P, Piazuelo MB, Camargo MC.

Source: Gastric Cancer. 2004;7(1):9-16.

Despite advances in surgical treatment and chemotherapy, gastric cancer remains a major global health burden. The most recent estimates show that it is the fourth most common cancer and the second most common cause of cancer deaths worldwide. Various etiologic factors have been linked with the disease. It is widely accepted that Helicobacter pylori infection and high salt intake are positively associated with this neoplastic process. Controversial associations have been found with smoking or drinking habits. In contrast, there is convincing evidence that the adequate consumption of fresh fruits and vegetables reduces the risk of gastric cancer. Prevention intervention trials involving antioxidant supplements and anti- H. pylori treatment have shown beneficial effects in preventing the progression of pathologic changes in the gastric mucosa. On the other hand, recent advances related to differences in the genotypes of the bacteria and in human cytokine polymorphisms would allow the design and implementation of large-scale screening programs to identify subjects at the highest risk of gastric cancer. Curing the infection in such subjects and supplying adequate amounts of antioxidants should prevent a neoplastic outcome, and this intervention should be monitored by endoscopic surveillance.

Green tea and gastrointestinal cancer risk

Authors: Borrelli, F., Capasso, R., Russo, A., Ernst, E.

Source: Aliment Pharmacol Ther; 19:5, 497-510

BACKGROUND: : Gastrointestinal cancer is one of the leading causes of cancer mortality in the world. Therefore, numerous efforts are being made to find chemoprotective substances able to reduce its incidence. Amongst these, green tea, one of the most popular beverages world-wide, has been reported to provide protective effects against gastrointestinal cancer.

AIM: : To critically evaluate all epidemiological studies reporting an association between green tea consumption and a reduced risk of gastrointestinal cancer.

METHODS: : Epidemiological studies of green tea consumption in relation to gastrointestinal cancer or preneoplastic lesions were identified through computerized literature searches using the following databases: Medline (Pubmed), Embase, Amed, CISCOM, Phytobase and Cochrane Library. Only epidemiological studies indicating the type of tea (green tea) and the site of either cancer or precancerous lesions (stomach or intestine) were included. No language restrictions were imposed.

RESULTS: : Twenty-one epidemiological investigations met our inclusion/exclusion criteria.

CONCLUSION: : These studies seemed to suggest a protective effect of green tea on adenomatous polyps and chronic atrophic gastritis formations. By contrast, there was no clear epidemiological evidence to support the suggestion that green tea plays a role in the prevention of stomach and intestinal cancer.

VEGF Receptor Phosphorylation Status and Apoptosis is Modulated by a Green Tea Component, Epigallocatechin-3-gallate (EGCG) in B cell Chronic Lymphocytic Leukemia.

Authors: Lee YK, Bone ND, Strege AK, Jelinek DF, Kay NE.

Source: Blood. 2004 Mar 2 [Epub ahead of print]

We recently reported that chronic lymphocytic leukemia (CLL) cells synthesize and release VEGF under normoxic and hypoxic conditions. CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2), suggesting that they use VEGF as a survival factor. To assess the mechanism of apoptosis resistance related to VEGF, we determined the impact of VEGF on CLL B cells, and we studied the impact of epigallocatechin (EGCG), a known receptor tyrosine kinase (RTK) inhibitor, on VEGF receptor status and viability of CLL B cells. VEGF165 significantly increased apoptotic resistance of CLL B cells and immunoblotting revealed that VEGF-R1 and VEGF-R2 are spontaneously phosphorylated on CLL B cells. EGCG significantly increased apoptosis/cell death in 8 of 10 CLL samples measured by annexin V/propidium iodide (PI) staining. The increase in annexin V/PI staining was accompanied by caspase 3 activation and PARP cleavage at low concentrations of EGCG (3 micro g/ml). Moreover, EGCG suppressed the proteins Bcl-2, XIAP and Mcl-1 in CLL B cells. Finally, EGCG (3-25 micro g/ml) suppressed VEGF-R1 and VEGF-R2 phosphorylation, albeit incompletely. Thus, these results suggest that VEGF signaling regulates survival signals in CLL cells and that interruption of this autocrine pathway results in caspase activation and subsequent leukemic cell death.

Energy balance in early breast cancer patients receiving adjuvant chemotherapy.

Authors: Harvie MN, Campbell IT, Baildam A, Howell A.

Source: Breast Cancer Res Treat. 2004 Feb;83(3):201-10.

Weight gain is a common problem amongst women receiving adjuvant chemotherapy for early breast cancer. We undertook a study to determine the causes of this weight gain. Prospective measurements of body mass and composition (skinfolds, bioelectrical impedance, total body potassium), energy balance (resting energy expenditure dietary intake, and physical activity), were determined in 17 women during and in the 6 months after commencing adjuvant chemotherapy. Women gained significant amounts of weight (5.0 +/- 3.8; p < 0.01) and body fat (7.1 kg +/- 4.5; p < 0.01) over the year. Waist circumference (5.1 +/- 4.5 cm; p < 0.01) and abdominal skinfold (16.2 +/- 10 mm; p < 0.01) were also increased but there was a decline in fat free mass (FFM); 1.7 +/- 2.5 kg. Women due to receive adjuvant chemotherapy had a greater resting energy expenditure (REE) compared with healthy subjects ( n = 21); 100.5 +/- 8.0% Harris Benedict compared to 94.5 +/- 8.4% Harris Benedict ( p = 0.05). REE declined by 3% during adjuvant chemotherapy ( p < 0.05), and remained depressed until at least 3 months posttreatment. There were no significant changes in dietary intake or physical activity over the year. Failure of women to reduce their energy intake to compensate for the decreased energy requirement may account for some of the weight gain. Treatment of adjuvant chemotherapy causes gain of body fat because of reduced energy expenditure, and the failure of women to reduce their energy intake to compensate for the decline in energy requirement during and in the 6 months posttreatment. Since weight gain impacts on survival, patients should be counselled to reduce energy intake and exercise during and after adjuvant treatment.

Analgesic effects of a soy-containing diet in three murine bone cancer pain models.

Authors: Zhao C, Wacnik PW, Tall JM, Johns DC, Wilcox GL, Meyer RA, Raja SN.

Source: J Pain. 2004 Mar;5(2):104-10.

Bone is a common metastatic site for prostate and breast cancer, and bone cancer is usually associated with severe pain. Traditional treatments for cancer pain can sometimes be ineffective or associated with side effects. Thus an increasing number of patients seek alternative therapies. In this study we investigated the analgesic effects of a soy diet on 3 experimental models of bone cancer pain. Mice were fed a diet in which the protein source was either soy or casein. After 1 week on the diet, sarcoma cells (NCTC 2472) were injected into the medullary cavity of the humeri, femur, or calcaneus. Experimenters blinded to diet of the animal assessed the pain behavior in these animals, forelimb grip force in the humerus model and paw withdrawal frequency to mechanical stimuli in the calcaneus and femur models. The effect of morphine on cancer-induced pain behavior was investigated in calcaneus and femur models. In addition, in the femur model, the effects of soy on tumor size and bone destruction were studied. The soy diet reduced secondary mechanical hyperalgesia in the femur model but had no effect on primary mechanical hyperalgesia in the calcaneus model or on movement-related hyperalgesia in the humerus model. No dietary impact was discerned in measurements of tumor size, bone destruction, and body weight in the femur model, suggesting that the soy diet had no effect on cancer growth. Morphine dose-dependently reduced hyperalgesia with no diet-based difference. These results suggest that a soy diet might provide analgesia in certain forms of hyperalgesia associated with bone cancer. PERSPECTIVE: The study raises the possibility of dietary supplements influencing aspects of cancer pain. Further research will help determine if use of nutritional supplements, such as soy proteins, can reduce opioid analgesic use in chronic pain states and help minimize the side effects associated with long term use of opioids.

Prevention of chemotherapy and radiation toxicity with glutamine.

Authors: Savarese, D. M., Savy, G., Vahdat, L., Wischmeyer, P. E., Corey, B.

Source: Cancer Treat Rev. 2003 Dec;29(6):501-13.

GOALS OF THE WORK: Malignancy produces a state of physiologic stress that is characterized by a relative deficiency of glutamine, a condition that is further exacerbated by the effects of cancer treatment. Glutamine deficiency may impact on normal tissue tolerance to antitumor treatment, and may lead to dose reductions and compromised treatment outcome. Providing supplemental glutamine during cancer treatment has the potential to abrogate treatment-related toxicity. We reviewed the available data on the use of glutamine to decrease the incidence and severity of adverse effects due to chemotherapy and/or radiation in cancer patients.

METHODS: We performed a search of the MEDLINE database during the time period 1980-2003, and reviewed the English language literature of both human and animal studies pertaining to the use of glutamine in subjects with cancer. We also manually searched the bibliographies of published articles for relevant references.

MAIN RESULTS: The available evidence suggests that glutamine supplementation may decrease the incidence and/or severity of chemotherapy-associated mucositis, irinotecan-associated diarrhea, paclitaxel-induced neuropathy, hepatic veno-occlusive disease in the setting of high dose chemotherapy and stem cell transplantation, and the cardiotoxicity that accompanies anthracycline use. Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury.

CONCLUSIONS: The role of glutamine in the prevention of chemotherapy and radiation-induced toxicity is evolving. Glutamine supplementation is inexpensive and it may reduce the incidence of gastrointestinal, neurologic, and possibly cardiac complications of cancer therapy. Further studies, particularly placebo-controlled phase III trials, are needed to define its role in chemotherapy-induced toxicity.

Cruciferous vegetables, mushrooms, and gastrointestinal cancer risks in a multicenter, hospital-based case-control study in Japan.

Authors: Hara M, Hanaoka T, Kobayashi M, Otani T, Adachi HY, Montani A, Natsukawa S, Shaura K, Koizumi Y, Kasuga Y, Matsuzawa T, Ikekawa T, Sasaki S, Tsugane S.

Source: Nutr Cancer. 2003; 46(2): 138-47.

We assessed the possible association of gastrointestinal cancers with cruciferous vegetables and mushrooms in a multicenter, hospital-based case-control study in an agricultural area of Japan. One hundred forty-nine cases and 287 controls for stomach cancer and 115 cases and 230 controls for colorectal cancer were matched by age, sex, and residential area. In stomach cancer, the protective effect of vegetables (consumption of total vegetable) was obscure, but it became clearer when we examined specific kinds of vegetables. Marginal associations were observed in the group of the highest consumption of Chinese cabbage (odds ratio [OR] = 0.61; 95% confidence interval [CI] = 0.35-1.07), broccoli (OR = 0.60; 95% CI = 0.34-1.08), Hypsizigus marmoreus (Bunashimeji) (OR = 0.57; 95% CI = 0.31-1.04) and Pholita nameko (Nameko) (OR = 0.56; 95% CI = 0.30-1.06). In colorectal cancer, we observed decreased risks from the highest tertile of total vegetables (OR = 0.22; 95% CI = 0.08-0.66) and low-carotene-containing vegetables (OR = 0.28; 95% CI = 0.08-0.77), and inverse associations were observed in the group of the highest consumption of broccoli (OR = 0.18; 95% CI = 0.06-0.58). Although the sample size was limited, subgroup analyses showed that the associations differed with the histopathological subtype. These findings suggest that cruciferous vegetables decrease the risk of both stomach and colorectal cancer, and that mushrooms are associated with a decreased risk of stomach cancer.

Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic.

Authors: Vucenik I, Shamsuddin AM.

Source: J Nutr. 2003 Nov;133(11 Suppl 1):3778S-3784S.

Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plant and mammalian cells. It was recently recognized to possess multiple biological functions. A striking anticancer effect of IP6 was demonstrated in different experimental models. Inositol is also a natural constituent possessing moderate anticancer activity. The most consistent and best anticancer results were obtained from the combination of IP6 plus inositol. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in a reversion to normal phenotype. Exogenously administered IP6 is rapidly taken into the cells and dephosphorylated to lower-phosphate inositol phosphates, which further interfere with signal transduction pathways and cell cycle arrest. Enhanced immunity and antioxidant properties can also contribute to tumor cell destruction. However, the molecular mechanisms underlying this anticancer action are not fully understood. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP6 holds great promise in our strategies for the prevention and treatment of cancer. IP6 plus inositol enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in a pilot clinical trial. The data strongly argue for the use of IP6 plus inositol in our strategies for cancer prevention and treatment. However, the effectiveness and safety of IP6 plus inositol at therapeutic doses needs to be determined in phase I and phase II clinical trials in humans.

Aqueous extract of herba Scutellaria barbatae, a chinese herb used for ovarian cancer, induces apoptosis of ovarian cancer cell lines.

Authors: Powell CB, Fung P, Jackson J, Dall'Era J, Lewkowicz D, Cohen I, Smith-McCune K.

Source: Gynecol Oncol. 2003 Nov;91(2):332-40.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California-San Francisco, 94143, San Francisco, CA, USA

Given the increasingly common use of complementary medicine in cancer patients, we tested the in vitro cytotoxicity of aqueous extracts of 15 traditional Chinese herbs with purported anticancer properties on ovarian and breast cancer cell lines.Cell viability after treatment with herbal extract was measured by metabolism of a tetrazolium substrate. Apoptosis was measured by nuclear and DNA fragmentation and Annexin V binding.One herb, Herba Scutellaria barbatae, was cytotoxic to 100% (11 of 11) of actively proliferating ovarian lines tested and 50% (2 of 4) of actively proliferating breast cell lines tested. Confluent cultures were resistant to killing by herb, whereas subconfluent cultures were sensitive. Resistant proliferating cell lines expressed higher levels of bcl2. Transfection of the most sensitive ovarian cancer cell line (A2780) with bcl2 resulted in a noticeable protection against apoptosis, but there was no protection in other transfected lines.These results will be useful in guiding future studies of herbal aqueous extracts, as well as providing information for clinicians when patients are concurrently using these herbs along with conventional cancer therapies.

Lentin, a novel and potent antifungal protein from shitake mushroom with inhibitory effects on activity of human immunodeficiency virus-1 reverse transcriptase and proliferation of leukemia cells.

Authors: Ngai PH, Ng TB.

Source: Life Sci. 2003 Nov 14;73(26):3363-74.

Department of Biochemistry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.

From the fruiting bodies of the edible mushroom Lentinus edodes, a novel protein designated lentin with potent antifungal activity was isolated. Lentin was unadsorbed on DEAE-cellulose, and adsorbed on Affi-gel blue gel and Mono S. The N-terminal sequence of lentin manifested similarity to endoglucanase. Lentin, which had a molecular mass of 27.5 kDa, inhibited mycelial growth in a variety of fungal species including Physalospora piricola, Botrytis cinerea and Mycosphaerella arachidicola. Lentin also exerted an inhibitory activity on HIV-1 reverse transcriptase and proliferation of leukemia cells.

Conjugated linoleic acid (CLA)-enriched milk fat inhibits growth and modulates CLA-responsive biomarkers in MCF-7 and SW480 human cancer cell lines.

Authors: Miller A, Stanton C, Murphy J, Devery R.

Source: Br J Nutr. 2003 Nov;90(5):877-85.

School of Biotechnology, Dublin City University, Dublin 9, Republic of Ireland.

Milk enriched in conjugated linoleic acid (CLA) was obtained from cows on pasture supplemented with full-fat rapeseeds (FFR; 2.26 g cis 9, trans 11 (c9,t11)-CLA/100 g fatty acid methyl esters) and full-fat soyabeans (1.83 g c9,t11-CLA100 g fatty acid methyl esters). A control milk fat (1.69 g c9,t11-CLA/100 g fatty acid methyl esters) was obtained from cows fed on pasture only. The present study assessed the potency of the CLA-enriched milk fats to modulate biomarkers that had previously been observed to respond to c9,t11-CLA in the MCF-7 and SW480 cell lines. Cell numbers decreased (P<0.05) by up to 61 and 58% following the incubation of MCF-7 and SW480 cells, respectively, for 4 d with milk fats (yielding CLA concentrations between 60.2 and 80.6 microM). The FFR milk fat, containing the highest CLA content, increased (P<0.05) [14C]arachidonic acid (AA) uptake into the monoacylglycerol fraction of MCF-7 and SW480 cells while it decreased (P<0.05) uptake into the phospholipid fraction of the latter. This milk fat also decreased (P<0.05) [14C]AA conversion to prostaglandin (PG) E2 while increasing conversion to PGF2alpha in both cell lines. All milk-fat samples increased (P<0.05) lipid peroxidation as measured by 8-epi-PGF2alpha in both cell lines. In SW480 cells the milk-fat samples decreased (P<0.05) bcl-2 and cytosolic glutathione levels while increasing (P<0.05) membrane-associated annexin V levels. All milk-fat samples decreased (P<0.05) the expression of ras in SW480 cells. These data suggest that milk-fat CLA was effective at modulating synthetic CLA-responsive biomarkers.

Activation of antitumor immunity by intratumor injection of biological preparations

Authors: Ebina T.

Source: Gan To Kagaku Ryoho. 2003 Oct;30(11):1555-8.

Division of Immunology, Miyagi Cancer Center Research Institute.

The antitumor effects of biological response modifiers (BRMs) in an experimental mouse model using a double grafted tumor system were analyzed. Some BRMs prevented metastases by utilizing the anti-tumor immunological cascade reactions, which activate macrophages in the body. The following BRMs were analyzed: PSK was a hot water extract of cultured mycelia from Coliolus versicolor and a protein bound beta-glucan. Lentinan was purified from fruit bodies of Lentinus erodes and is a beta-glucan. The agaricus preparation was extracted from fruit bodies of Agaricus blazei and a protein-bound alpha-, beta-glucan. The M2 fraction was extracted from mycelia of Tricholoma matsutake and was a protein bound alpha-glucan. M1 fraction was purified from mycelia of T. matsutake and was an alpha-glucan. PSK cured both primary and metastatic tumors in the double grafted tumor system. Lentinan did not inhibit the growth of either primary or metastatic tumors. Agaricus preparation cured a primary tumor and inhibited the growth of a metastatic tumor. The M2 fraction prepared from Matsutake inhibited the growth of both primary and metastatic tumors. The M1 fraction did not inhibit either primary or metastatic tumors. Immunosuppressive acidic protein (IAP) is produced by activated macrophages. The PSK, Agaricus preparation and M2 fraction of the Matsutake preparation induced IAP but the lentinan and M1 fraction did not.

Gamma (gamma) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (gamma) expression in SW 480 human colon cancer cell lines.

Authors: Campbell SE, Stone WL, Whaley SG, Qui M, Krishnan K.

Source: BMC Cancer. 2003 Oct 1;3(1):25. Epub 2003 Oct 01.

Division of Hematology-Oncology, Department of Internal Medicine, East Tennessee State University and James H, Quillen VA Medical Center, Johnson City, TN, USA 37614. krishnak@etsu.edu

BACKGROUND: Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of gamma-tocopherol is higher than alpha-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used alpha-tocopherol. Recent epidemiological, experimental and molecular studies suggest that gamma-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied alpha-tocopherol. gamma-Tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor gamma (PPARgamma) is a promising molecular target for colon cancer prevention. Upregulation of PPARgamma activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARgamma ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both alpha and gamma tocopherol on the expression of PPARgamma mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines.

RESULTS: We have discovered that the alpha and gamma isoforms of vitamin E upregulate PPARgamma mRNA and protein expression in the SW480 colon cancer cell lines. gamma-Tocopherol is a better modulator of PPARgamma expression than alpha-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, gamma-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of alpha-tocopherol. CONCLUSION: Our data suggest that both alpha and gamma tocopherol can upregulate the expression of PPARgamma which is considered an important molecular target for colon cancer chemoprevention. We show that the expression of PPARgamma mRNA and protein are increased and these effects are more pronounced with gamma-tocopherol. gamma-Tocopherol's ability to upregulate PPARgamma expression and achieve higher intracellular concentrations in the colonic tissue may be relevant to colon cancer prevention. We also show that the intracellular concentrations of gamma-tocopherol are several fold higher than alpha-tocopherol. Further work on other colon cancer cell lines are required to quantitate differences in the ability of these forms of vitamin E to induce apoptosis, suppress cell proliferation and act as PPAR ligands as well as determine their effects in conjunction with other chemopreventive agents. Upregulation of PPARgamma by the tocopherols and in particular by gamma-tocopherol may have relevance not only to cancer prevention but also to the management of inflammatory and cardiovascular disorders.

Lycopene oxidation product enhances gap junctional communication.

Authors: Aust O, Ale-Agha N, Zhang L, Wollersen H, Sies H, Stahl W.

Source: Food Chem Toxicol. 2003 Oct;41(10):1399-407.

Institut fur Biochemie und Molekularbiologie I, Heinrich-Heine-Universitat Dusseldorf, Postfach 10 10 07, D-40001, Dusseldorf, Germany

Carotenoids as well as their metabolites and oxidation products stimulate gap junctional communication (GJC) between cells, which is thought to be one of the protective mechanisms related to cancer-preventive activities of these compounds. Increased intake of lycopene by consumption of tomatoes or tomato products has been epidemiologically associated with a diminished risk of prostate cancer. Here, we report a stimulatory effect of a lycopene oxidation product on GJC in rat liver epithelial WB-F344 cells. The active compound was obtained by complete in vitro oxidation of lycopene with hydrogen peroxide/osmium tetroxide. For structural analysis high performance liquid chromatography, gas chromatography coupled with mass spectrometry, ultraviolet/visible-, and infrared spectrophotometry were applied. The biologically active oxidation product was identified as 2,7,11-trimethyl-tetradecahexaene-1,14-dial. The present data indicate a potential role of lycopene degradation products in cell signaling enhancing cell-to-cell communication via gap junctions.

Turning an 'Achilles' Heel' into an asset - activation of HIF-1alpha during angiostatic therapy will increase tumor sensitivity to iron-catalyzed oxidative damage.

Authors: McCarty MF.

Source: Med Hypotheses. 2003 Oct;61(4):509-11.

Pantox Laboratories, San Diego, California, USA

During angiostatic therapy, tumor hypoxia will activate the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), and will select for mutations which up-regulate the activity of this factor. This adaptation will increase tumor angiogenic capacity, while aiding the survival of poorly nourished cancer cells. A further effect of HIF-1alpha is to increase expression of transferrin receptors. The natural antimalarial drug artemisinin is selectively toxic to iron-loaded cells (such as malarial parasites), and it has recently been suggested that, inasmuch as many cancers overexpress transferrin receptors, such cancers might be treatable with a regimen comprised of iron supplementation and high-dose artemisinin. Thus, it can be anticipated that many tumors which evolve relative resistance to angiostatic therapy will be selectively susceptible to attack by the iron-loading/artemisinin strategy.

Prospective study of serum vitamin E levels and esophageal and gastric cancers.

Authors: Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, Mark SD.

Source: J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6.

Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-8314, USA. ptaylor@mail.nih.gov

Participants in the General Population Trial, a randomized nutrition intervention trial in Linxian, China, who received a combination of selenium, beta-carotene, and vitamin E supplements, had statistically significantly lower cancer mortality rates than those who did not receive the supplements. In the current study, we used a case-cohort design to examine the association between pre-trial serum vitamin E levels and the risks of developing esophageal and gastric cancers during the trial. We measured serum alpha- and gamma-tocopherol and cholesterol levels in 1072 case patients with incident esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), or gastric noncardia cancer (GNCC) and in 1053 control subjects. The relative risks for comparisons of the highest to the lowest quartiles of serum alpha-tocopherol were 0.63 (95% confidence interval [CI] = 0.44 to 0.91) for ESCC, 0.84 (95% CI = 0.55 to 1.26) for GCC, and 2.05 (95% CI = 0.89 to 4.75) for GNCC. Serum gamma-tocopherol level was not associated with the incidence of any of these cancers. Our findings provide support for the role of alpha-tocopherol in the etiology of upper gastrointestinal cancers.

Genistein reduces NF-kappa B in T lymphoma cells via a caspase-mediated cleavage of I kappa B alpha.

Authors: Baxa DM, Yoshimura FK.

Source: Biochem Pharmacol. 2003 Sep 15;66(6):1009-18.

Department of Immunology and Microbiology, Wayne State University, 540 E. Canfield Ave., Detroit, MI 48201, USA.

The transcription factor NF-kappa B is elevated in murine T-cell lymphoma lines compared with normal thymic lymphocytes, and may play a role in the neoplastic transformation of these cells. When T lymphoma cells were treated with the soy isoflavone genistein, a marked reduction in nuclear NF-kappa B levels was detectable predominantly for the p50/p50 homodimer and p50/p65 heterodimer. To examine the mechanism by which NF-kappa B is reduced by genistein, we analyzed the NF-kappa B inhibitor, I kappa B alpha, and detected a 34 kDa cleavage product Delta I kappa B alpha, which was induced by genistein in a dose-dependent manner. Our observation that a pan-caspase inhibitor could inhibit the induction of Delta I kappa B alpha by genistein suggested that caspase activity was responsible for this cleavage product. In support of this idea, we detected an increase in caspase-3 activity in response to increasing time of genistein exposure. When the induction of Delta I kappa B alpha was prevented, we detected no reduction of NF-kappa B levels by genistein. These results support a direct role for Delta I kappa B alpha in the reduction of NF-kappa B by genistein. To determine the effect of genistein on some NF-kappa B target gene products, we examined the antiapoptotic proteins Bcl-2, Bcl-X(L), A1, and cIAP-1. Only changes in A1 and cIAP-1 levels were affected with significant reductions in response to genistein. Generation of the repressive activity of Delta I kappa B alpha on NF-kappa B is a novel mechanism for the reduction of this transcription factor by genistein and the possible effect this may have on the ability of genistein to induce apoptosis in tumor cells.

Micronutrients, antioxidants, and carcinoma of the gallbladder.

Authors: Shukla VK, Adukia TK, Singh SP, Mishra CP, Mishra RN.

Source: J Surg Oncol. 2003 Sep;84(1):31-35.

Department of Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.

OBJECTIVES: Nutrient deficiency in developing countries can be considered a significant contributory factor modifying the multistage process of carcinogenesis. Studies from different parts of the world have shown the deficiency of various micronutrients to be significantly associated with cancer. This study was undertaken to test the above hypothesis in patients with carcinoma of the gallbladder.

METHODS: Selenium (Se), zinc (Zn), copper (Cu), manganese (Mn), ascorbic acid (vitamin C), and alpha-tocopherol (vitamin E) were estimated in the serum, bile, and gallbladder tissue of 30 patients each of carcinoma of the gallbladder (group-I), cholelithiasis (group-II), and only in the serum of 30 age- and sex-matched healthy controls (group-III). The minerals were analyzed by atomic absorption spectrophotometer and vitamins by spectrophotometry.

RESULTS: The mean serum levels of Se, Zn, Mn, vitamin E, and vitamin C were significantly lower (P < 0.001) in group-I when compared with groups II and III. The mean biliary levels of Se and Zn (0.29, 3.45 mg/L) were reduced significantly (P < 0.001) in group-I when compared with group II (0.51, 5.2 mg/L). Mean tissue levels of Se and Zn were also significantly lower (P < 0.001) in group I (2.75, 43.09 microg/g) compared to group II (3.90, 61.37 microg/g). However, no significant difference was observed in tissue concentration of Mn, vitamin C, and vitamin E. Cu levels and Cu/Zn ratio showed a highly significant (P < 0.001) increase in serum, bile, and gallbladder tissue in carcinoma of the gallbladder compared to the other two groups.

CONCLUSIONS: The data supports an association between lower levels of Se, Zn, vitamin E, and risk of carcinoma of the gallbladder and suggest that Cu/Zn ratio could be a useful parameter in evaluating the patients of carcinoma of the gallbladder. J. Surg. Oncol. 2003;84:31-35. Copyright 2003 Wiley-Liss, Inc.

Cardiorespiratory fitness and cancer mortality in Japanese men: a prospective study.

Authors: Sawada SS, Muto T, Tanaka H, Lee IM, Paffenbarger RS Jr, Shindo M, Blair SN.

Source: Med Sci Sports Exerc. 2003 Sep;35(9):1546-50.

Tokyo Gas Health Promotion Center, Tokyo, Japan. s-sawada@tokyo-gas.co.jp

PURPOSE: Limited data are available on the relationship between cardiorespiratory fitness and cancer mortality. We evaluated the cardiorespiratory fitness and risk of cancer mortality in Japanese men.

METHODS: A total of 9039 men (19-59 yr) who were given a submaximal exercise test and a health examination between 1982 and 1988 and were followed for mortality up to 1999. Cardiorespiratory fitness was measured using a cycle ergometer test, and maximal oxygen uptake was estimated. RESULTS: The mean follow-up period was slightly more than 16 yr, producing a total of 148,491 person-years of observation. There were 231 deaths, with 123 deaths due to cancer. Relative risk (RR) and 95% confidence interval (95%CI) for cancer mortality were obtained using the Cox proportional hazards model. Taking into consideration age, systolic blood pressure, body mass index, smoking habit, and alcohol habit and using the lowest physical fitness group as the reference, the RR (95% CI) for increasing quartiles of fitness were 0.75(0.48-1.16), 0.43(0.25-0.74) and 0.41(0.23-0.74); P < 0.001 for trend.

CONCLUSION: Low cardiorespiratory fitness is associated with cancer mortality in Japanese men.

Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro.

Authors: Chen HH, Zhou HJ, Fang X.

Source: Pharmacol Res. 2003 Sep;48(3):231-6.

Department of Pharmacology and Toxicology, College of Pharmacology, Zhejiang University, Zhejiang 310031, Hangzhou, PR China. chenh552@163.com

Artemisinin derivatives artesunate (ART) and dihydroartemisinin are remarkable anti-malarial drugs with low toxicity to humans. In the present investigation, we find they also inhibited tumor cell growth and suppressed angiogenesis in vitro. The anti-cancer activity was demonstrated by inhibition (IC(50)) of four human cancer cell lines: cervical cancer Hela, uterus chorion cancer JAR, embryo transversal cancer RD and ovarian cancer HO-8910 cell lines growth by the MTT assay. IC(50) values ranged from 15.4 to 49.7 microM or from 8.5 to 32.9 microM after treatment with ART or dihydroartemisinin for 48 h, indicating that dihydroartemisinin was more effective than ART in inhibiting cancer cell lines. The anti-angiogenic activities were tested on in vitro models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells. We investigated the inhibitory effects of ART and dihydroartemisinin on HUVE cells proliferation by cell counting, migration into the scratch wounded area in HUVE cell monolayers and microvessel tube-like formation on collagen gel. The results showed ART and dihydroartemisinin significantly inhibited angiogenisis in a dose-dependent form in range of 12.5-50 microM and 2.5-50 microM, respectively. They indicated that dihydroartemisinin was more effective than ART in inhibiting angiogenesis either. These results and the known low toxicity are clues that ART and dihydroartemisinin may be promising novel candidates for cancer chemotherapy.

Anti-tumour and immuno-stimulating activities of the fruiting bodies of Paecilomyces japonica, a new type of Cordyceps spp.

Authors: Shin KH, Lim SS, Lee S, Lee YS, Jung SH, Cho SY.

Source: Phytother Res. 2003 Aug;17(7):830-3.

Natural Products Research Institute, Seoul National University, Seoul, Korea. khshin@snu.ac.kr

The anti-tumor and immuno-stimulating activities of the fruiting bodies of Paecilomyces japonica (PJ), grown on silk-worm larvae and of Cordyceps sinensis (CS), a wild form of Cordyceps Fungi, were investigated. Ethanol extracts of both fungi, when administered for 9 consecutive days, at 50 and 100 mg/kg i.p., caused a significant increase in life span and a significant decrease in tumor weights and volumes, in mice inoculated with Sarcoma-180 tumor cells. Both fungal extracts were demonstrated to exhibit phagocytosis enhancing activity as measured by carbon clearance in mice. PJ extracts, when administered i.p. at 50 mg/kg/day for 3 consecutive days, exhibited a significant enhancement of phagocytosis, its potency as expressed by the regression coefficient ratio, RCtr/RCc, being 1.64 (the phagocytosis index = 2). This was approximately the same for that of zymosan (RCtr/RCc = 1.55, PI = 2), a typical phagocytosis enhancer, whereas CS extracts exhibited a moderate phagocytosis enhancing activity at the same dose level (RCtr/RCc = 1.30, PI = 1). Both fungal extracts caused a significant increase in an acid phosphatase activity, representing lysosomal enzymes, in macrophages at 20 and 100 micro g/ml in vitro, in compliance with in vivo results. These results suggest that the anti-tumor activity of both fungi might be related to an immuno-stimulating function. Copyright 2003 John Wiley & Sons, Ltd.

Effect of dietary pectin on the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium

Authors: Lim, B. O., Lee, S. H., Park, D. K., Choue, R. W.

Source: Biosci Biotechnol Biochem, 67:8, 1706-12

The present study explores the dietary effect of pectin on the MLN lymphocyte functions of mice with dextran sulfate sodium (DS)-induced colitis. We found that the immunoglobulin (Ig)A level in mesenteric lymph node (MLN) lymphocytes was high, while the IgE level was lower, in mice fed with pectin than in those fed with cellulose. Interestingly, the fecal IgA concentration of the pectin-fed mice was significantly higher than that of the cellulose-fed mice. The concentrations of interferon-gamma and interleukin (IL)-2 treated with concanavalin A (ConA) were significantly higher in the pectin-fed group than in the cellulose-fed group. Although dietary pectin did not affect the IL-4 and IL-10 levels, the activation-induced IL-4 and IL-10 secretion was lower in MLN cells of the pectin-fed mice than of the cellulose-fed mice following DS-induced colitis. Based on these findings, we propose that the effect of dietary pectin on mice with DS-induced colitis is mediated by the manipulation of Th1 cells. Furthermore, the inhibitory effect of IL-4 and IL-10 by dietary pectin may play an important role in promoting a change in Th1/Th2 balance toward Th1-dominant immunity.

Phytoestrogen intake and endometrial cancer risk.

Authors: Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM.

Source: J Natl Cancer Inst. 2003 Aug 6;95(15):1158-64.

Northern California Cancer Center, Union City, CA 94587, USA. phornros@nccc.org

BACKGROUND: The development of endometrial cancer is largely related to prolonged exposure to unopposed estrogens. Phytoestrogens (i.e., weak estrogens found in plant foods) may have antiestrogenic effects. We evaluated the associations between dietary intake of seven specific compounds representing three classes of phytoestrogens (isoflavones, coumestans, and lignans) and the risk of endometrial cancer.

METHODS: In a case-control study from the greater San Francisco Bay Area, we collected dietary information from 500 African American, Latina, and white women aged 35-79 years who were diagnosed with endometrial cancer between 1996 and 1999 and from 470 age- and ethnicity-matched control women identified through random-digit dialing. Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

RESULTS: Isoflavone (OR = 0.59, 95% CI = 0.37 to 0.93 for the highest versus lowest quartile of exposure) and lignan (OR = 0.68, 95% CI = 0.44 to 1.1) consumptions were inversely related to the risk of endometrial cancer. These associations were slightly stronger in postmenopausal women (OR = 0.44, 95% CI = 0.26 to 0.77 and OR = 0.57, 95% CI = 0.34 to 0.97 for isoflavones and lignans, respectively). Obese postmenopausal women consuming relatively low amounts of phytoestrogens had the highest risk of endometrial cancer (OR = 6.9, 95% CI = 3.3 to 14.5 compared with non-obese postmenopausal women consuming relatively high amounts of isoflavones); however, the interaction between obesity and phytoestrogen intake was not statistically significant.

CONCLUSION: Some phytoestrogenic compounds, at the levels consumed in the typical American-style diet, are associated with reduced risk of endometrial cancer.

Induction of rat hepatic and intestinal UDP-glucuronosyltransferases by naturally occurring dietary anticarcinogens.

Authors: Van Der Logt EM, Roelofs HM, Nagengast FM, Peters WH.

Source: Carcinogenesis. 2003 Jul 17 [Epub ahead of print].

Department of Gastroenterology, University Medical Centre St Radboud, Nijmegen, The Netherlands.

Gastrointestinal tumours are among the most common malignancies in Western society, the majority of which is associated with dietary and lifestyle factors. Many dietary or lifestyle factors have been identified which may have toxic or carcinogenic properties. However, also several dietary compounds able to reduce gastrointestinal cancer rates both in humans and animals have been characterised. Though the exact mechanism leading to the anticarcinogenic action of these compounds is not fully known, it has been demonstrated that this chemopreventive capacity may be due to elevation of the glutathione S-transferase detoxification enzymes. Now we investigated the effect of several anticarcinogens on the gastrointestinal UDP-glucuronosyltransferase (UGT) enzymes. Diets of male Wistar rats were supplemented with ellagic acid, ferulic acid, Brussels sprouts, quercetin, alpha-angelicalactone, tannic acid, coumarin, fumaric acid, curcumin and flavone separately, and combinations of alpha-angelicalactone and flavone. Hepatic and intestinal (proximal-, mid-, distal small intestine and colon) UGT enzyme activities were quantified by using 4-nitrophenol and 4-methylumbelliferone as substrates. All anticarcinogens tested increased UGT enzyme activity with both substrates, at least at one of the five different sites investigated. alpha-Angelicalactone, coumarin and curcumin showed enhanced UGT enzyme activities at all five sites. Both small and large intestinal UGT enzyme activities were increased by quercetin, alpha-angelicalactone, coumarin, curcumin and flavone. Except for tannic acid, all agents induced hepatic UGT enzyme activity. Furthermore, dietary administration of alpha-angelicalactone and flavone, given individually or in combination, enhanced the UGT detoxification system in the liver and to a lesser extent in intestine. In conclusion, induction of gastrointestinal UGT enzyme activities after consumption of dietary anticarcinogens, may contribute to a better detoxification of potentially carcinogenic compounds and subsequently to the prevention of gastrointestinal cancer.

Inhalation aromatherapy during radiotherapy: results of a placebo-controlled double-blind randomized trial.

Authors: Graham PH, Browne L, Cox H, Graham J.

Source: J Clin Oncol. 2003 Jun 15;21(12):2372-6.

Cancer Care Centre, St George Hospital, Gray St, Kogarah, Australia, 2217, grahamp@sesahs.nsw.gov.au.

PURPOSE: To determine whether the inhalation of aromatherapy during radiotherapy reduces anxiety.

PATIENTS AND METHODS: Three hundred thirteen patients undergoing radiotherapy were randomly assigned to receive either carrier oil with fractionated oils, carrier oil only, or pure essential oils of lavender, bergamot, and cedarwood administered by inhalation concurrently with radiation treatment. Patients underwent assessment by the Hospital Anxiety and Depression Scale (HADS) and the Somatic and Psychological Health Report (SPHERE) at baseline and at treatment completion.

RESULTS: There were no significant differences in HADS depression or SPHERE scores between the randomly assigned groups. However, HADS anxiety scores were significantly lower at treatment completion in the carrier oil only group compared with either of the fragrant arms (P =.04).

CONCLUSION: Aromatherapy, as administered in this study, is not beneficial.

Topical application of honey in the management of radiation mucositis. A Preliminary study.

Authors: Biswal BM, Zakaria A, Ahmad NM.

Source: Support Care Cancer. 2003 Apr;11(4):242-8. Epub 2003 Feb 19.

Division of Radiotherapy and Oncology, Department of Nuclear Medicine, Radiotherapy and Oncology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia, biswa@kb.usm.my

BACKGROUND. The aim of this study was to evaluate the effect of pure natural honey on radiation-induced mucositis.

PATIENTS AND METHODS. Forty patients diagnosed with head and neck cancer requiring radiation to the oropharyngeal mucosal area were divided in to two groups to receive either radiation alone or radiation plus topical application of pure natural honey. Patients were treated using a 6-MV linear accelerator at a dose rate of 2 Gy per day five times a week up to a dose of 60-70 Gy. In the study arm, patients were advised to take 20 ml of pure honey 15 min before, 15 min after and 6 h post-radiation therapy. Patients were evaluated every week for the development of radiation mucositis using the Radiation Therapy Oncology Group (RTOG) grading system.

MAIN RESULTS. There was significant reduction in the symptomatic grade 3/4 mucositis among honey-treated patients compared to controls; i.e. 20% versus 75% ( p 0.00058). The compliance of honey-treated group of patients was better than controls. Fifty-five percent of patients treated with topical honey showed no change or a positive gain in body weight compared to 25% in the control arm ( p 0.053), the majority of whom lost weight.

CONCLUSIONS. Topical application of natural honey is a simple and cost-effective treatment in radiation mucositis, which warrants further multi-centre randomised trials to validate our finding.

Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy.

Authors: Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio A, Leonetti C, Jandolo B, Cognetti F, Bove L.

Source: J Clin Oncol 2003 Mar 1;21(5):927-31

Neuroscience Department, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy. pace@ifo.it

PURPOSE: The aim of this study is to evaluate the neuroprotective effect of antioxidant supplementation with vitamin E in patients treated with cisplatin chemotherapy.

METHODS: Between April 1999 and October 2000, forty-seven patients were randomly assigned to either group one, which received vitamin E supplementation during cisplatin chemotherapy, or to group two, which received cisplatin chemotherapy alone. Alpha-tocopherol (vitamin E; 300 mg/d) was administered orally before cisplatin chemotherapy and continued for 3 months after the suspension of treatment. For preclinical studies, nude mice carrying the human melanoma tumor were treated with cisplatin alone or in combination with vitamin E.

RESULTS: Twenty-seven patients completed six cycles of cisplatin chemotherapy: 13 patients in group one and 14 patients in group two. The incidence of neurotoxicity was significantly lower in group one (30.7%) than it was in group two (85.7%; P <.01). The severity of neurotoxicity, measured with a comprehensive neurotoxicity score based on clinical and neurophysiological parameters, was significantly lower in patients who were supplemented with vitamin E than in patients who were not supplemented with vitamin E (2 v 4.7, P <.01). The results of the preclinical studies showed that when cisplatin was combined with vitamin E, no differences were observed in tumor weight inhibition, tumor growth delay, or life span as compared with treatment with cisplatin alone.

CONCLUSION: Supplementation of patients receiving cisplatin chemotherapy with vitamin E decreases the incidence and severity of peripheral neurotoxicity.

Using splines to detect changes in PSA doubling times.

Authors: Guess B, Jennrich R, Johnson H, Redheffer R, Scholz M.

Source: Prostate 2003 Feb 1;54(2):88-94

Healing Touch Oncology, Marina del Rey, California.

BACKGROUND: PSA doubling time (PSADT) can predict the likelihood of clinical progression in patients with biochemical relapse after surgery or radiation for prostate cancer. Changes in PSA doubling time in response to therapy may be of clinical or investigational significance. How does one estimate PSADT before and after the initiation of therapy and determine if any change is statistically significant or simply the result of random variation? These are the type of questions addressed.

METHODS: Our technique uses a best-fitting spline (i.e., a broken-line approximation) to a graph of log PSA on time to estimate PSADTs before and after treatment initiation. A linear regression program is used to produce the fit and to evaluate the statistical significance of any change in PSADT. This method differs from previous methods in that it uses all the data, exploits the continuity of PSA at the time of treatment initiation, and allows one to make statistical significance statements about specific individuals.

RESULTS: Our technique is illustrated with data from a pilot clinical trial using a nutritional supplement in 12 men with prostate cancer. A detailed analysis of the first patient shows how the data are handled, how two lines of computer code are sufficient to fit the spline model, and how the doubling times and statistical significance of a change are read from the computer output. In the study, 9 of 12 patients had a statistically significant increase in doubling time. Because the study is preliminary and used only to illustrate our method, no medical discussion of the study is included. The last section of the study, in part expository, is devoted to explaining the underlying principles for those who may want to know not only what to do, but why it works.

CONCLUSIONS: The method presented here for determining changes in PSADT is both simple and broadly applicable. It allows the evaluation of the size and statistical significance of an observed change or increase in PSADT in response to therapy for prostate cancer. It can be done using essentially any statistical software and widely accepted statistical methods. Prostate 54: 88-94, 2003. Copyright 2002 Wiley-Liss, Inc.

Upregulation of galectins-1 and -3 in human colon cancer and their role in regulating cell migration.

Authors: Hittelet A, Legendre H, Nagy N, Bronckart Y, Pector JC, Salmon I, Yeaton P, Gabius HJ, Kiss R, Camby I.

Source: Int J Cancer 2003 Jan 20;103(3):370-9

Laboratory of Gastroenterology, Erasmus Hospital, Brussels, Belgium.

To probe the potential contribution of beta-galactoside-contributing epitopes and receptor proteins (gal-1 and gal-3) to colon malignancy, we first examined the expression of galectins and binding sites in clinical specimens by lectin and immunohistochemistry. Sixty-seven colonic surgical resections were studied, including 10 normal, 10 mild dysplasias, 10 severe dysplasias and 37 cancers. gal-1 and gal-3 were expressed in variable amounts in the epithelial cells and the connective tissue of normal colon. Their expression significantly increased with the degree of dysplasia, suggesting that gal-1 and gal-3 and their binding sites are related to malignant progression, while gal-8 has been associated with suppressor activity. To study the functional aspects, the influence of these galectins on the migration of 4 human colorectal cancer cell lines (HCT-15, LoVo, DLD-1, CoLo201) was studied. In agreement with histopathologic monitoring, these tumor cells were found to produce gal-3, while only CoLo201 was positive for gal-1. Except for DLD-1 and gal-1, the lines exhibited gal-1 binding sites on the surface, prompting study by computer-assisted videomicroscopy of the effect on cell migration of the presence of galectin on the culture substrate. The level of cell migration for HCT-15, LoVo and CoLo201 cells was significantly reduced by 0.15 microg/cm(2) gal-1, and the presence of a blocking antibody at least reduced this effect. gal-3 significantly reduced cell migration in all 4 of the in vitro cell lines. Copyright 2002 Wiley-Liss, Inc.

A Prospective Study of Intake of Fish and Marine Fatty Acids and Prostate Cancer.

Authors: Augustsson K, Michaud DS, Rimm EB, Leitzmann MF, Stampfer MJ, Willett WC, Giovannucci E.

Source: Cancer Epidemiol Biomarkers Prev 2003 Jan;12(1):64-67

Departments of Nutrition [K. A., D. S. M., E. B. R., M. F. L., M. J. S., W. C. W., E. G.] and Epidemiology [E. B. R., M. J. S., W. C. W., E. G.], Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital [E. B. R., M. J. S., W. C. W.], Boston, Massachusetts.

Experimental studies suggest that marine fatty acids have an antitumor effect on prostate tumor cells. The aim of this study was to investigate whether high consumption of fish and marine fatty acids reduces the risk of prostate cancer in humans. We followed 47,882 men participating in the Health Professionals Follow-up Study. Dietary intake was assessed in 1986, 1990, and 1994, using a validated food frequency questionnaire. During 12 years of follow-up, 2,482 cases of prostate cancer were diagnosed, of which 617 were diagnosed as advanced prostate cancer including 278 metastatic prostate cancers. Eating fish more than three times per week was associated with a reduced risk of prostate cancer, and the strongest association was for metastatic cancer (multivariate relative risk, 0.56; 95% confidence interval, 0.37-0.86, compared with infrequent consumption, i.e., less than twice per month). Intake of marine fatty acids from food showed a similar but weaker association. Each additional daily intake of 0.5 g of marine fatty acid from food was associated with a 24% decreased risk of metastatic cancer. We found that men with high consumption of fish had a lower risk of prostate cancer, especially for metastatic cancer. Marine fatty acids may account for part of the effect, but other factors in fish may also play a role.

Cell cycle progression and cytokine gene expression of human peripheral blood mononuclear cells modulated by Agaricus blazei.

Authors: Kuo YC, Huang YL, Chen CC, Lin YS, Chuang KA, Tsai WJ.

Source: J Lab Clin Med 2002 Sep;140(3):176-87

National Research Institute of Chinese Medicine, the Institute of Biology, and the Department of Nutrition and Food Sciences, Fu-Jen University, Taipei, Taiwan. kuo9111@cma23.nricm.edu.tw

We selected Agaricus blazei Murill, used in the treatment of tissue inflammation and cancer in traditional Chinese medicine, to test its immunopharmacological activity. The effects of A. blazei extracted fractions (AB-BDM-1 to AB-BDM-10) on human peripheral blood mononuclear cell (PBMC) proliferation were determined on the basis of the uptake of tritiated thymidine. The results indicated that AB-BDM-2 fraction suppressed PBMC proliferation activated with phytohemagglutinin. The inhibitory action of AB-BDM-2 did not involve direct cytotoxicity. Cell-cycle analysis indicated that AB-BDM-2 arrested the cell-cycle progression of activated PBMCs from the G1 transition to the S phase. In an attempt to further localize the point in the cell cycle where arrest occurred, we examined a set of key regulatory events leading to the G1/S boundary, including gene expression of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and cyclin D. AB-BDM-2 suppressed, in activated PBMCs, the production and messenger RNA (mRNA) expression of IL-2, IL-4, IFN-gamma, and cyclin D in dose-dependent fashion. AB-BDM-2 did not affect nitric oxide production or levels of inducible nitric oxide synthetase mRNA in PBMCs stimulated with PHA. The suppressant effects of AB-BDM-2 on the proliferation of PBMC activated by PHA therefore appear to be mediated, at least in part, through inhibition of early transcripts of PBMCs, especially those of important cytokines IL-2, IL-4, and IFN-gamma, cyclin D, and the arrest of cell-cycle progression in the cells. We suggest that immunomodulatory agents are contained in AB-BDM-2 separated from A. blazei.

Fibre intake and laryngeal cancer risk

Authors: C. Pelucchi, R. Talamini, F. Levi, C. Bosetti, C. La Vecchi, E. Negri1, M. Parpine, S. Franceschi

Source: Annals of Oncology 14:162-167, 2003

Background: Consumption of vegetables, fruit and whole grain cereals has been inversely related to laryngeal cancer risk. Among the potential protective agents found in these foods, information on dietary fibres and laryngeal cancer risk are scanty.

Patients and methods: A multi-centric, hospital-based case–control study was conducted on 527 patients with squamous-cell carcinoma of the larynx and 1297 non-neoplastic controls. Cases and controls, frequency matched by age, sex and study centre, were interviewed using a validated food frequency questionnaire.

Results: Compared with the lowest quintile of fibre intake, the odds ratios (ORs) for the highest quintile were 0.3 [95% confidence interval (CI) 0.2–0.4] for total fibre, 0.3 (95% CI 0.2–0.5) for soluble non-cellulose polysaccharides (NCP) and for total insoluble fibre, including cellulose (OR = 0.3, 95% CI 0.2–0.4) and insoluble NCP (OR = 0.4, 95% CI 0.3–0.7). The ORs were 0.2 (95% CI 0.1–0.4) for fibre from vegetables, 0.5 (95% CI 0.3–0.7) from fruit and 1.1 (95% CI 0.6–1.9) from grains. The inverse association observed was similar among different subsites of laryngeal cancer, and consistent across strata of various covariates.

Conclusions: This study found a strong inverse association between fibre intake and laryngeal cancer risk, which points to fibre as one of the beneficial components of vegetables and fruit.

Colonic anti-inflammatory mechanisms of conjugated linoleic acid.

Authors: BASSAGANYA-RIERA J, HONTECILLAS R, BEITZ DC.

Source: Clin Nutr 2002 Dec;21(6):451-9

Department of Animal Sciences, Iowa State University, Ames, Iowa, USA

Conjugated linoleic acid (CLA) is a mixture of positional (e.g. 7,9; 9,11; 10,12; 11,13) and geometric (cis or trans) isomers of octadecadienoic acid. This compound was first shown to prevent mammary carcinogenesis in murine models. Later investigations uncovered a number of additional health benefits, including decreasing atherosclerosis and inflammation while enhancing immune function. The mechanisms of action underlying these biological properties are not clearly understood. The aim of this review is to highlight recent advances in CLA research related to experimental inflammatory bowel disease. In addition, two possible mechanisms of action (i.e. endoplasmic and nuclear) were discussed in detail in the context of enteric inflammatory disorders. Conjugated linoleic acid was first implicated in down-regulating the generation of inducible eicosanoids (i.e. PGE(2) and LTB(4)) involved in early micro-inflammatory events (endoplasmic). More recently, CLA has been shown to modulate the expression of genes regulated by peroxisome proliferator-activated receptors (PPARs; nuclear). In pigs, prolonged dietary CLA treatment stimulated the expression of PPAR-gamma in the muscle. Thus, evidence supporting both mechanistic theories of CLA acting through eicosanoid synthesis and PPAR activity is available. The further understanding of the anti-inflammatory mechanisms of action of CLA may yield novel nutritional therapies for enteric inflammation.

Galectin-3 expression alters adhesion, motility and invasion in a lung cell line (DLKP), in vitro.

Authors: O'Driscoll L, Linehan R, Liang YH, Joyce H, Oglesby I, Clynes M.

Source: Anticancer Res 2002 Nov-Dec;22(6A):3117-25

National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. Lorraine.ODriscoll@dcu.ie

BACKGROUND: Galectin-3, a beta-galactosidase-binding protein, is involved in regulating many physiological and pathological cellular processes. The significance of galectin-3 in human lung and nasal carcinoma cells has not yet been elucidated.

MATERIALS AND METHODS: Using RT-PCR and Western blotting techniques, the constitutive level of galectin-3 in the human non-small cell lung carcinoma cell line, DLKP, was investigated. Following galectin-3 cDNA transfection into these cells, growth, toxicity, adhesion, motility and invasion assays were used to investigate the relevance of galectin-3 over-expression.

RESULTS: Galectin-3 over-expression did not induce a multi-drug resistance phenotype or significantly affect cell growth rate, but it did result in enhanced (i) adhesion to extracellular matrix components; (ii) cell motility; and (iii) in vitro invasiveness. Furthermore, studies of RPMI-2650 variants suggest that galectin-3 expression correlates with nasal carcinoma cell invasiveness.

CONCLUSION: Our results suggest that galectin-3 expression levels in both lung and nasal tumour cells may play a role in cell motility, invasion, and metastasis.

Differential expression of galectin-3 in medullary thyroid carcinoma and C-cell hyperplasia.

Authors: Faggiano A, Talbot M, Lacroix L, Bidart JM, Baudin E, Schlumberger M, Caillou B.

Source: Clin Endocrinol (Oxf) 2002 Dec;57(6):813-9

Department of Pathology, Commissariat a l'Energie Atomique LRC29V, Institut Gustave Roussy, F-94805 Villejuif Cedex, France. afaggiano@hotmail.com

OBJECTIVE AND DESIGN: Galectin-3 is a beta-galactoside-binding protein that plays a role in cell adhesion and tumour progression. It was shown recently to diagnose malignant follicular thyroid lesions accurately. The reliability of this marker in the differential diagnosis between medullary thyroid carcinoma and C-cell hyperplasia was studied by immunohistochemistry.

PATIENTS: Tissue specimens were obtained from 34 patients belonging to families with medullary thyroid carcinoma who underwent prophylactic thyroidectomy for RET gene mutation and/or abnormally increased plasma calcitonin levels.

RESULTS: Galectin-3 was expressed in 23 of 25 cases of medullary thyroid carcinoma and in none of the nine cases of C-cell hyperplasia only, giving a sensitivity of 92% and a specificity of 100% for the diagnosis of carcinoma. A significant association was found between higher galectin-3 expression and occurrence of lymph node metastases (P < 0.05).

CONCLUSIONS: Galectin-3 is a reliable diagnostic marker of medullary thyroid carcinoma, and its use may provide relevant information for prognosis and therapy.

Effects of red ginseng upon postoperative immunity and survival in patients with stage III gastric cancer.

Authors: Suh SO, Kroh M, Kim NR, Joh YG, Cho MY.

Source: Am J Chin Med 2002;30(4):483-94

Department of Surgery, Korea University College of Medicine, 126-1 5th-Ga, Anam-Dong Sungbuk-Gu, Seoul, 136-705, Korea.

In this paper, we present evidence that the red ginseng powder from Panax ginseng C.A. Meyer inhibits the recurrence of AJCC stage III gastric cancer and shows immunomodulatory activities during postoperative chemotherapy, after a curative resection with D2 lymph node dissection. Flow cytometric analyses for peripheral T-lymphocyte subsets showed that the red ginseng powder restored CD4 levels to the initial preoperative values during postoperative chemotherapy. Depression of CD3 during postoperative chemotherapy was also inhibited by the red ginseng powder ingestion. This study demonstrated a five-year disease free survival and overall survival rate that was significantly higher in patients taking the red ginseng powder during postoperative chemotherapy versus control (68.2% versus 33.3%, 76.4% versus 38.5%, respectively, p < 0.05). In spite of the limitation of a small number of patients (n = 42), these findings suggest that red ginseng powder may help to improve postoperative survival in these patients. Additionally, red ginseng powder may have some immunomodulatory properties associated with CD3 and CD4 activity in patients with advanced gastric cancer during postoperative chemotherapy.

Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin.

Authors: Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A.

Source: J Natl Cancer Inst 2002 Dec 18;94(24):1854-62

P. Nangia-Makker, V. Hogan, S. Baccarini, L. Tait, A. Raz, Wayne State University, School of Medicine, and Department of Pathology, Karmanos Cancer Institute, Detroit, MI.

BACKGROUND: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro.

METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test.

RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner.

CONCLUSIONS: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer.

Tomatoes, lycopene intake, and digestive tract and female hormone-related neoplasms

Authors: La Vecchia C.

Source: Exp Biol Med (Maywood) 2002 Nov;227(10):860-3

Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. garimoldi@marionegri.it

Tomato consumption showed a consistent inverse relation with the risk of digestive tract neoplasms in Italy in an integrated series of studies conducted in the 1980s. Another series of case-control studies was conducted between 1992 and 1999 in different areas of Italy. Cases were patients below age 80 with incident, histologically confirmed cancer of the oral cavity and pharynx (n = 754), esophagus (n = 304), colorectum (n = 1953), breast (n = 2529), and ovary (n = 1031). The comparison group involved, overall, over 5000 patients below age 80 with acute, non-neoplastic, nonhormone-related diseases, unrelated to long-term diet modifications and admitted to the same network of hospitals. Information was collected in hospital by trained interviewers using a validated food frequency questionnaire, including 78 foods or groups of foods, various alcoholic beverage, and fat-intake pattern. The multivariate relative risk (RR) of oral, pharyngeal, and esophageal cancer decreased across subsequent levels of lycopene intake to reach 0.7 (95% confidence interval [CI] 0.4-1.0) for oral and pharyngeal, and 0.7 (95% CI 0.4-1.1) for esophageal cancer in the highest quintile of intake. Both trends in risk were of borderline statistical significance. With reference to colorectal, breast, and ovarian cancer, although no consistent association was observed for lycopene (RR = 1.0 for colorectal, 1.2 for breast, and 1.1 for ovary in the highest quintile), tomato intake was inversely and significantly related with colorectal cancer (RR = 0.8). The inverse relation between lycopene and upper digestive tract neoplasms was not explained by alcohol or tobacco, sociodemographic factors, or total energy intake. The interpretation of such an inverse relation, however, remains open to discussion because it may be related to an effect of lycopene due to its antioxidant effect and/or a potential role of lycopene in decreasing insulin growth factor I, which is a promoter in the process of carcinogenesis.

Inhibition of Human Colon Carcinoma Development by Lentinan from Shiitake Mushrooms (Lentinus edodes).

Authors: Ng ML, Yap AT.

Source: J Altern Complement Med 2002 Oct;8(5):581-9

Department of Microbiology, National University of Singapore, Singapore.

OBJECTIVES: Lentinan was extracted from shiitake mushrooms (Lentinus edodes) via a new cost-effective procedure that resulted in high purity (88%) and yield. Unlike previous reports whereby the lentinan was given parenterally, in this study the emphasis was on the oral administration of lentinan. The goal is to document whether the efficacy of the antitumor property is still expressed through this route of administration.

DESIGN: Initial study on the action of lentinan was conducted using murine lymphoma (K36) cells in a AKR mouse model. Further investigation on the effectiveness of the extracted lentinan was then performed using human colon-carcinoma cell lines in mice. Six established human colon-carcinoma cell lines segregated into three groups of different degrees of differentiation were used in this study. One group was not fed (control) and the second group was prefed with lentinan for 7 days prior to inoculations with the cancer cells. The size of the tumors that developed was rated after 1 month.

RESULTS: Significant regression in tumor formation was observed in prefed mice compared to control (unfed) mice when K36 or human colon-carcinoma cells were used. Significant reductions in the size of the tumors were observed in mice prefed with lentinan. Follow-up investigation proceeded with the use of nude mice (athymic). Lymphocytes extracted from AKR mice prefed with lentinan for 7 days were inoculated into the nude mice. This was then followed by inoculation of the human colon-carcinoma cell lines into these mice. Much smaller tumors were formed in nude mice inoculated with lymphocytes, in contrast to the larger tumor formed in nude mice without lymphocytes inoculation.

CONCLUSION: This study showed that the antitumor property of lentinan was maintained with oral administration. In addition, "primed" lymphocytes, when given passively to immunodeficient mice, were able to retard the development of tumors in these mice.

Expression of human intestinal mucin is modulated by the beta-galactoside binding protein galectin-3 in colon cancer.

Authors: Dudas SP, Yunker CK, Sternberg LR, Byrd JC, Bresalier RS.

Source: Gastroenterology 2002 Sep;123(3):817-26

Gastrointestinal Cancer Research Laboratory, Henry Ford Health Sciences Center, Detroit, Michigan; and The Department of Gastrointestinal Medicine and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background & Aims: Alterations in the production of the beta-galactoside binding protein galectin-3 and of MUC2 intestinal mucin have been independently correlated with the malignant behavior of human colon cancer cells. MUC2 mucin is a major ligand for galectin-3, and colon cancer cells that differ quantitatively in MUC2 expression may also vary in expression of galectin-3. The current study was designed to investigate the relationship between galectin-3 production and MUC2 mucin synthesis by human colon cancer cells.

METHODS: The effect of galectin-3 on MUC2 mucin production was assessed by stable transfection of sense and antisense galectin-3 expression constructs under the control of constitutive or tetracycline-inducible promoters into human colon cancer cells. Galectin-3 and MUC2 expression were determined by fluorescence-activated cell sorter (cell surface galectin-3), Western and Northern analysis (galectin-3, MUC2), and gel filtration of secreted high-weight glycoprotein (MUC2). In vitro results were confirmed in vivo by analysis of cecal xenografts in athymic mice.

RESULTS: Colon cancer cells with high levels of galectin-3 also had high levels of MUC2 mucin, whereas those with low galectin-3 levels had low MUC2 levels. Alterations in galectin-3 levels by expression of sense or antisense galectin-3 constructs resulted in parallel alterations of MUC2 protein and RNA. Induction of antisense to galectin-3 in vivo was associated with decreases in both galectin-3 and MUC2 protein in cecal xenografts.

CONCLUSIONS: The beta-galactoside binding protein galectin-3 modulates the expression of its major ligand MUC2 mucin in human colon cancer cells. This may have important implications for understanding the role of galectin-3 in colon cancer metastasis.

Immunological study on the antitumor effects of fungus polysaccharides compounds

Authors: Liu C, Gao P, Qian J, Yan W.

Source: Wei Sheng Yan Jiu. 2000 May 30;29(3):178-80.

Institute of Food Safety Control and Inspection, Ministry of Health, Beijing 100021, China.

Fungus polysaccharides compounds (FPC) are the mixture of procyanidins oligomers, glycyrrhetinicacid and polysaccharides of hericium erinaceus, lentinus edodes and poria cocos. The antitumor effects of FPC and its immunity regulating effects as an immunostimulant on the mice burdened with sarcoma 180 (S-180) were studied. FPC (100, 200 and 400 mg/kg BW) was gavaged to mice for 31 days. S-180 was transplanted to these mice on the 21th day. Lentinus edodes group was gavaged 200 mg/kg BW saccharine of lentinus edodes. The results showed that FPC could inhibit the growth of S-180 effectively. The inhibitory rates were 37.74%, 44.73% and 48.32% respectively. The antineoplastic activity of FPC (200 mg/kg. BW) was more effective than polysaccharide of lentinus edodes at the same dose. In S-180 burdened mice, the percentage of L3T4 and the ratio of L3T4/Lyt-2, NK activity and the induced IL-2, IFN-gamma levels were decreased significantly compared with the normal control group. As an immunostimulant, FPC could increase the percentage of L3T4 and the ratio of L3T4/Lyt-2 in S-180 burdened mice, but had no significant effects on the percentage of Lyt-2. Polysaccharide of lentinus edodes alone could also increase the immunity competence of mice burdened with S-180, but was not better than that of FPC at the same dose. It could be concluded that the compound of antineoplastic component could be synergetic.

Modulation of the lung colonization of B16-F1 melanoma cells by citrus pectin.

Authors: Platt D; Raz A

Source: J Natl Cancer Inst 1992 Mar 18;84(6):438-42.

CONTEXT: Studies have shown that the galactoside-containing simple sugars and anti-galactoside-binding lectin antibodies may affect experimental tumor cell metastasis. However, the limited number of reagents used thus far necessitate further observations. PURPOSE: Natural citrus pectin (CP) and pH-modified CP (MCP), rich in galactose residues, were used to study the involvement of carbohydrates containing galactoside residues in cellular interaction in vitro and in lung colonization in vivo of B16-F1 melanoma cells.

METHODS: B16-F1 melanoma cells were incubated with various concentrations of CP and MCP. Their ability to form homotypic aggregation in vitro and tumor lung colonization in vivo in 8-week-old female C57BL/6 mice was then analyzed.

RESULTS: The CP binds to the surface of B16-F1 melanoma cells; this binding can be inhibited by lactose at a concentration of 0.15 M. Intravenous injection of the murine B16-F1 melanoma cells with the natural CP resulted in a significant increase (up to threefold) in the appearance of tumor colonies in the lung and in increased homotypic aggregation properties of the cells, while injection of MCP significantly decreased B16-F1 experimental metastasis (greater than 90%).

CONCLUSIONS: Tumor galactoside-binding proteins mediate cellular recognition by linking oligosaccharides with terminal D-galactoside residues on adjacent cells. Successful interference with such a process with MCP may lead to a reduced ability to form tumor cell emboli and metastasis.

IMPLICATIONS: These findings imply that the galactose-containing carbohydrate side chains of CP might mimic or compete with the natural ligand(s) of the tumor galactoside-binding protein (gal-lectin) and thus affect cellular interactions relevant for metastasis.

Selenium prevents tumor development in a rat model for chemical carcinogenesis.

Authors: Bjorkhem-Bergman L, Torndal UB, Eken S, Nystrom C, Capitanio A, Larsen EH, Bjornstedt M, Eriksson LC.

Source: Carcinogenesis. 2004 Sep 30

Previous studies in animals and humans have shown that selenium compounds can prevent cancer development. In this work we studied the tumor preventive effect of selenium supplementation, administrated as selenite, in the initiation, promotion and progression phases in a synchronised rat model for chemically induced hepatocarcinogenesis, the resistant hepatocyte model. Selenite in supra-nutritional but subtoxic doses (1 and 5 ppm) was administrated to the animals through the drinking water. Such supplementation during the initiation phase did not have tumor preventive effect. However, selenite treatment during the promotion phase decreased the volume fraction of preneoplastic liver nodules from 38% in control animals to 25% (1 ppm) and 14% (5 ppm) in the selenite-supplemented groups. In addition the cell proliferation within the nodules decreased from 42% in control to 22% (1 ppm) and 17% (5 ppm). Immunohistochemical staining for the selenoenzyme thioredoxin reductase 1 (TrxR1) revealed an increased expression of the enzyme in liver nodules compared to the surrounding tissue. The activity was reduced to 50% in liver homogenates from selenium treated animals but the activity of the selenoenzyme glutathione peroxidase was essentially unaltered. Selenite treatment (5 ppm) during the progression phase resulted in significantly lower volume fraction of liver tumors (14% compared to 26 %) along with a decrease of cell proliferation within the tumors (34 % compared to 63 %). Taken together our data indicate that the carcinogenetic process may be prevented by selenium supplementation both during the promotion and the progression phase.

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