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May 2002

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Prostate Cancer

U.S. dietary exposures to heterocyclic amines.

Heterocyclic amines (HAs) formed in fried, broiled or grilled meats are potent mutagens that increase rates of colon, mammary, prostate and other cancers in bioassay rodents. Studies of how human dietary HA exposures may affect cancer risks have so far relied on fairly crudely defined HA-exposure categories. Recently, an integrated, quantitative approach to HA-exposure assessment (HAEA) was developed to estimate compound-specific intakes for particular individuals based on corresponding HA-concentration estimates that reflect their meat-type, intake-rate, cooking-method and meat-doneness preferences. This method was applied in the present study to U.S. national Continuing Survey of Food Intakes by Individuals (CSFII) data on meats consumed and cooking methods used by >25,000 people, after adjusting for underreported energy intake and conditional on meat-doneness preferences estimated from additional survey data. The U.S. population average lifetime time-weighted average of total HAs consumed was estimated to be approximately 9 ng/kg/day, with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) estimated to comprise about two thirds of this intake. Pan-fried meats were the largest source of HA in the diet and chicken the largest source of HAs among different meat types. Estimated total HA intakes by male vs. female children were generally similar, with those by (0- to 15-year-old) children approximately 25% greater than those by (16+-year-old) adults. Race-, age- and sex-specific mean HA intakes were estimated to be greatest for African American males, who were estimated to consume approximately 2- and approximately 3-fold more PhIP than white males at ages <16 and 30+ years, respectively, after considering a relatively greater preference for more well-done items among African Americans based on national survey data. This difference in PhIP intakes may at least partly explain why prostate cancer (PC) kills approximately 2-fold more African American than white men, in view of experimental data indicating that PhIP mutates prostate DNA and causes prostate tumors in rats.

J Expo Anal Environ Epidemiol 2001 May-Jun;11(3):155-68

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells.

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1) CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer.

Oncogene 2001 May 24;20(23):2927-36

Fruit and vegetable intakes and prostate cancer risk.

BACKGROUND: There is extensive and consistent evidence that high fruit and vegetable intakes are associated with decreased risks of many cancers, but results for prostate cancer risk have been inconsistent. We studied the associations of fruit and vegetable intakes with prostate cancer risk in a population-based, case-control study of men under 65 years of age. METHODS: Case participants were 628 men from King County (Seattle area), WA, who were newly diagnosed with prostate cancer. Control participants were 602 men recruited from the same underlying population and frequency matched to case participants by age. Self-administered food-frequency questionnaires were used to assess diet over the 3- to 5-year period before diagnosis or recruitment. Daily nutrient intakes were calculated by use of a nutrient database with recently updated analytic values for carotenoids. Odds ratios for prostate cancer risk associated with foods and nutrients were calculated by use of unconditional logistic regression. RESULTS: No associations were found between fruit intake and prostate cancer risk. The adjusted odds ratio (ORs) for the comparison of 28 or more servings of vegetables per week with fewer than 14 servings per week was 0.65 (95% confidence interval [CI] = 0.45-0.94), with a two-sided P for trend =.01. For cruciferous vegetable consumption, adjusted for covariates and total vegetable intake, the OR for comparison of three or more servings per week with less than one serving per week was 0.59 (95% CI = 0.39-0.90), with a two-sided P for trend =.02. The OR for daily intake of 2000 microg or more lutein plus zeaxanthin compared with an intake of less than 800 microg was 0.68 (95% CI = 0.45-1.00). CONCLUSION: These results suggest that high consumption of vegetables, particularly cruciferous vegetables, is associated with a reduced risk of prostate cancer.

J Natl Cancer Inst 2000 Jan 5;92(1):61-8

Mechanisms of anti-carcinogenesis by indole-3-carbinol. Studies of enzyme induction, electrophile-scavenging, and inhibition of aflatoxin B1 activation.

The induction of oxidation and conjugation enzymes, the scavenging of carcinogen electrophiles, and the inhibition of aflatoxin B1 (AFB1) activation were examined as possible mechanisms of anti-carcinogenesis by indole-3-carbinol (I3C). Liver microsomal 7-ethoxycoumarin O-deethylase and 7-ethoxyresorufin O-deethylase activities were not induced significantly in rainbow trout fed diets containing 500-2000 ppm I3C for 8 days compared to trout fed the control diet. Furthermore, no detectable changes in the specific contents of cytochrome P-450 isozymes LM2 and LM4b, as measured by Western-blotting and immunoquantitation, were found in liver microsomes following dietary I3C administration. Dietary I3C had no significant effect on liver microsomal uridine diphosphate-glucuronyl-transferase activity, measured using the substrates 1-naphthol and testosterone, or on cytosolic glutathione S-transferase activity, measured using the substrate styrene oxide. The ability of I3C or its acid reaction products (RXM; generated by the reaction of I3C with HCl) to act as scavengers for the direct alkylating agent AFB1-8,9-Cl2 was examined. Addition of I3C or RXM to in vitro incubations did not inhibit the covalent binding of AFB1-8,9-Cl2 to calf thymus DNA. Kinetic analyses of microsome-mediated binding of AFB1 to DNA in vitro indicated that RXM inhibited the metabolic activation of AFB1. RXM increased the apparent Km for the AFB1-DNA binding reaction without changing the associated Vmax; the apparent Km values at 0, 3.5, 35, and 350 microM RXM were 35, 38, 66 and 86 microM for trout liver microsomes. RXM also inhibited the activation of AFB1 by rat liver microsomes, but I3C was not an effective inhibitor against AFB1-DNA binding mediated by either rat or trout liver microsomes. The results of the present study indicate that inhibition of microsome-activated AFB1 binding to DNA by I3C products may be of significant importance in I3C inhibition of hepatocarcinogenesis in trout and other species. The inhibition of carcinogen activation by I3C is contrasted with the mechanism of anti-carcinogenesis by beta-naphthoflavone, which involves induction of xenobiotic metabolizing enzymes.

Biochem Pharmacol 1990 Jan 1;39(1):19-26

A prospective study of dietary fat and risk of prostate cancer.

BACKGROUND: The strong correlation between national consumption of fat and national rate of mortality from prostate cancer has raised the hypothesis that dietary fat increases the risk of this malignancy. Case-control and cohort studies have not consistently supported this hypothesis. PURPOSE: We examined prospectively the relationship between prostate cancer and dietary fat, including specific fatty acids and dietary sources of fat. We examined the relationship of fat consumption to the incidence of advanced prostate cancer (stages C, D or fatal cases) and to the total incidence of prostate cancer. METHODS: We used data from the Health Professionals Follow-up Study, which is a prospective cohort of 51529 U.S. men, aged 40 through 75, who completed a validated food-frequency questionnaire in 1986. We sent follow-up questionnaires to the entire cohort in 1988 and 1990 to document new cases of a variety of diseases and to update exposure information. As of January 31, 1990, 300 new cases of prostate cancer, including 126 advanced cases, were documented in 47855 participants initially free of diagnosed cancer. The Mantel-Haenszel summary estimator was used to adjust for age and other potentially confounding variables. Multiple logistic regression was used to estimate relative risks (RRs) when controlling simultaneously for more than two covariates. RESULTS: Total fat consumption was directly related to risk of advanced prostate cancer (age- and energy-adjusted RR = 1.79, with 95% confidence interval [CI] = 1.04-3.07, for high versus low quintile of intake; P [trend] = .06). This association was due primarily to animal fat (RR = 1.63; 95% CI = 0.95-2.78; P [trend] = .08), but not vegetable fat. Red meat represented the food group with the strongest positive association with advanced cancer (RR = 2.64; 95% CI = 1.21-5.77; P = .02). Fat from dairy products (with the exception of butter) or fish was unrelated to risk. Saturated fat, monounsaturated fat, and alpha-linolenic acid, but not linoleic acid, were associated with advanced prostate cancer risk; only the association with alpha-linolenic acid persisted when saturated fat, monounsaturated fat, linoleic acid, and alpha-linolenic acid were modeled simultaneously (multivariate RR = 3.43; 95% CI = 1.67-7.04; P [trend] = .002). CONCLUSION: The results support the hypothesis that animal fat, especially fat from red meat, is associated with an elevated risk of advanced prostate cancer. IMPLICATIONS: These findings support recommendations to lower intake of meat to reduce the risk of prostate cancer. The potential roles of carcinogens formed in cooking animal fat and of alpha-linolenic acid in the progression of prostate cancer need to be explored.

J Natl Cancer Inst 1993 Oct 6;85(19):1571-9

Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study.

BACKGROUND: Large international variations in rates of prostate cancer incidence and mortality suggest that environmental factors have a strong influence on the development of this disease. The purpose of this study was to identify predictive variables for prostate cancer mortality in data from 59 countries. METHODS: Data on prostate cancer mortality, food consumption, tobacco use, socioeconomic factors, reproductive factors, and health indicators were obtained from United Nations sources. Linear regression models were fit to these data. The influence of each variable fit in the regression models was assessed by multiplying the regression coefficient b by the 75th (X75) and 25th (X25) percentile values of the variable. The difference, bX75 - bX25, is the estimated effect of the variable across its interquartile range on mortality rates measured as deaths per 100000 males aged 45 to 74 years. Reported P values are two-sided. RESULTS: Prostate cancer mortality was inversely associated with estimated consumption of cereals (bX75 - bX25 = -7.31 deaths; P = .001), nuts and oilseeds (bX75 - bX25 = -1.72 deaths; P = .003), and fish (bX75 - bX25 = -1.47 deaths; P = .001). In the 42 countries for which we had appropriate data, soy products were found to be significantly protective (P = .0001), with an effect size per kilocalorie at least four times as large as that of any other dietary factor. Besides variables related to diet, we observed an association between prostate cancer mortality rates and a composite of other health-related, sanitation, and economic variables (P = .003). CONCLUSIONS: The specific food-related results from this study are consistent with previous information and support the current dietary guidelines and hypothesis that grains, cereals, and nuts are protective against prostate cancer. The findings also provide a rationale for future study of soy products in prostate cancer prevention trials.

J Natl Cancer Inst 1998 Nov 4;90(21):1637-47

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