LE Magazine May 2002
Page 4 of 4
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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