Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis

The chemopreventive efficacy of lycopene and curcumin with regard to prostate carcinogenesis was investigated using 3,2'-dimethyl-4-aminobiphenol (DMAB)- and 2-amino-1-methylimidazo[4,5-b]pyridine (PhIP)-induced rat ventral prostate cancer models. Three 60 week experiments with male F344 rats were carried out. In the first DMAB was given for the first 20 weeks and lycopene or curcumin were administered concomitantly or subsequently at dietary doses of 15 and 500 p.p.m., respectively. In the second experiment lycopene and curcumin were given to rats pretreated with DMAB at doses of 5, 15 or 45 p.p.m. or 100 or 500 p.p.m. In the third PhIP was selected as an initiator for prostate carcinogenesis and administered for 20 weeks. Rats were then fed a diet containing lycopene at a dose of 45 p.p.m. or curcumin at a dose of 500 p.p.m. or both together. Chemopreventive effects of lycopene and curcumin on development of DMAB-induced ventral prostate carcinomas were observed only in the first experiment and no confirmation of inhibition potential was obtained in the following studies. Neither summational nor synergistic chemoprevention was evident. It is concluded from the present data that, overall, neither lycopene nor curcumin can consistently prevent rat prostate carcinogenesis.     

Chemoprevention of 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine-induced colon carcinogenesis by 1-O-hexyl-2,3,5-trimethylhydroquinone after initiation with 1,2-dimethylhydrazine in F344 rats

The aim of this study is to investigate the chemopreventive effects of the synthetic phenolic antioxidant 1-O-hexyl-2,3, 5-trimethylhydroquinone (HTHQ) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colon carcinogenesis in rats after initiation with 1,2-dimethylhydrazine (DMH) in male F344 rats. Groups of 20-22, 6-week-old male F344 rats were given four subcutaneous injections of 40 mg/kg body wt of DMH during the initial 4 weeks. They were then maintained on powdered basal diet containing 0.03% PhIP alone, PhIP together with 0.5 or 0.125% HTHQ, 0.5 or 0.125% HTHQ alone or basal diet for 32 weeks. A small number (1.1 +/- 1.1/rat) of colon tumors were induced by DMH treatment alone. After initiation with DMH, the number of colon tumors was greatly increased to 8.3 +/- 5.6 by the administration of PhIP. Additional treatment with HTHQ dose-dependently decreased the multiplicity of colon adenocarcinomas to 4.9 +/- 2.8 and 2.6 +/- 1.4 with 0.125 and 0.5%, respectively. This treatment similarly reduced atypical hyperplasias of the ventral prostate. Furthermore, HTHQ significantly reduced the multiplicity of duodenal adenocarcinomas induced by DMH + PhIP or DMH alone. Immunohistochemically, HTHQ was revealed to suppress PhIP-DNA adduct formation in the epithelial cells of the colon and prostate in a separate 2 weeks experiment. The present results clearly showed that HTHQ has chemopreventive potential for PhIP-associated colon and prostate carcinogenesis. The observed inhibition may largely be due to interference with PhIP-DNA adduct formation. In addition, HTHQ has been demonstrated to inhibit duodenal carcinogenesis in the post-initiation stage.     

The dietary charred meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine acts as both a tumor initiator and promoter in the rat ventral prostate

Exposure of Fisher344 rats to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine in cooked meat, causes cancer in the rat ventral prostate, while sparing the dorsolateral and anterior lobes. Uncovering the molecular mechanisms of the lobe specificity of PhIP-induced rat prostate cancer may provide clues to the pathogenesis of human prostate cancer, which is also lobe selective. We examined the prostate and other organs for mutation frequencies using transgenic Fisher344 rats (Big Blue rats) after PhIP treatment. After PhIP treatment for as early as 4 weeks, the colon, spleen, seminal vesicles, and all lobes of the prostate had significantly elevated mutation frequencies compared with the saline-treated control group, and the differences became even greater after 8 weeks. G:C --> T:A transversions were the predominant type of mutation. After 8 weeks of treatment with PhIP, the Ki-67 index was increased (P < 0.001) in the ventral prostate, but not in the dorsolateral or anterior prostate. An increase in the number of stromal mast cells and macrophages was seen in the ventral prostate, but not in the other prostatic lobes. The apoptotic index also increased in the ventral lobe only. The increased proliferation and cell death in response to PhIP indicates that in addition to PhIP acting as an "initiator" of cancer, PhIP is also acting like an organ- and lobe-specific tumor "promoter." The prostate lobe-specific infiltration of mast cells and macrophages in response to PhIP suggests a potential new mechanism by which this dietary compound can increase cancer risk-by prompting inflammation.     

Protection against 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine cytotoxicity and DNA adduct formation in human prostate by glutathione S-transferase P1

The prostate has been identified as a target for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced carcinogenesis. Humans are exposed to PhIP through ingestion of well-done cooked meats, and there is evidence from epidemiological studies that implicates red meat consumption in prostate carcinogenesis. The alpha and pi class isoforms of glutathione S-transferases (GSTs) have been shown to inhibit adduction of activated PhIP metabolites to DNA in cell-free systems. In humans, silencing of GST pi(GSTP1) through CpG island hypermethylation is found in nearly all prostate carcinomas and is believed to be an early event in prostate carcinogenesis. We hypothesized that suppressed GSTP1 expression in prostate cells would increase their vulnerability to cytotoxicity and DNA adduct formation mediated by activated PhIP metabolites. To test this hypothesis, the human prostate adenocarcinoma cell line, LNCaP, which contains a silenced GSTP1 gene, was genetically modified to constitutively express high levels of GSTP1. Both LNCaP and LNCaP-GSTP1 cells exposed to N-OH-PhIP, but not parent PhIP, for 24 h showed a dose-dependent decrease in cell viability. GSTP1-overexpressing cells had LC50s 30-40% higher than cells transfected with the vector alone. PhIP-DNA adducts isolated from LNCaP-derived cells and primary human prostate tissue cultures exposed to N-OH-PhIP were analyzed by liquid chromatography/electrospray ionization mass spectrometry. Primary cultures of human prostate tissue and LNCaP-GSTP1 cells had approximately 50% lower adduct levels than parental LNCaP and vector control cells. Bioactivation assays using LNCaP cytosols showed that enzymatic activation of N-OH-PhIP to a DNA binding species was dependent on ATP and could be inhibited by recombinant human GSTP1 in the presence of glutathione. This evidence confirms that N-OH-PhIP can be bioactivated to a DNA binding species in human prostate and human prostate-derived cells. These observations provide the basis for using LNCaP and LNCaP-GSTP1 cells as a model system for studying the role of this enzyme in protection against N-OH-PhIP induced DNA damage in prostate carcinogenesis. Loss of GSTP1 expression in human prostate may, therefore, enhance its susceptibility to carcinogenic insult by compounds such as N-OH-PhIP. Conversely, induction of GSTs in early-stage prostate carcinogenesis may be a useful protective strategy.     

Dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced prostate carcinogenesis in CYP1A-humanized mice

To develop a relevant mouse model for prostate cancer prevention research, we administered a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), to CYP1A-humanized mice. In comparison with mouse Cyp1a2, human CYP1A2 preferentially activates PhIP to a proximate carcinogen. Following a single oral dose of PhIP (200 mg/kg body weight), we observed inflammation, atrophy of acini, low-grade prostatic intraepithelial neoplasia (PIN; after 20 weeks), and high-grade PIN (HgPIN; after 30 to 50 weeks) in dorsolateral, ventral, and coagulating anterior prostate glands of these mice. These lesions were androgen receptor positive and featured the loss of expression of the basal cell marker p63 and the tumor suppressor PTEN. Similar to human prostate carcinogenesis, glutathione S-transferase P1 (GSTP1) expression was lost or partially lost in HgPIN. E-Cadherin expression was also lost in HgPIN. The expression of DNA methyltransferase 1 was elevated, possibly to enhance promoter hypermethylation for the silencing of GSTP1 and E-cadherin. Prostate carcinogenesis was promoted by a high-fat stress diet, resulting in HgPIN that developed earlier and in advanced lesions displayed features consistent with carcinoma in situ. This dietary carcinogen-induced prostate cancer model, recapitulating important features of early human prostate carcinogenesis, constitutes a new experimental system for prostate cancer research.     

High susceptibility of the ACI and spontaneously hypertensive rat (SHR) strains to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) prostate carcinogenesis

Carcinogenic responses in the prostate to 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP) were compared among seven rat strains (F344, ACI, Spontaneously Hypertensive Rat (SHR), Sprague-Dawley (SD), Wistar, Lewis and Brown Norway (BN)). Ten-week-old animals of each strain were given PhIP at 400 ppm in the diet for 20 weeks then maintained until week 54. The final survival rates were 92, 92, 83, 75, 67, 42 and 42%, respectively, and the SHR strain showed the highest sensitivity with regard to development of prostatic intraepithelial neoplasias (PINs) in the ventral prostate. With regard to the induction of adenocarcinomas of the ventral prostate, the ACI strain was most sensitive, whereas Lewis and F344 rats were relatively resistant. No adenocarcinomas were found in the dorsolateral or anterior prostate or seminal vesicles in any of the strains. The levels of serum testosterone and estrogen, PhIP-DNA adducts and cell kinetics did not correlate with the development of ventral prostatic lesions and thus other factors are presumably responsible for the variations in susceptibility. The present data indicate that ACI and SHR rats are appropriate strains for experimental investigation of PhIP-induced prostate carcinogenesis.     

Organ dependent enhancement of rat 3,2'-dimethyl-4-aminobiphenyl (DMAB) carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): positive effects on the intestine but not the prostate

In order to evaluate tumor enhancing effects of the heterocyclic carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), doses of 100 and 300 p.p.m. PhIP were given for 40 weeks to male F344 rats, which initially received 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB shows a similar carcinogenic organ spectrum to that of PhIP, including the prostate and colon. PhIP alone at a dose of 300 p.p.m. resulted in the development of prostate and intestine cancers. Furthermore, among the DMAB-treated group, enhancement of intestinal carcinogenesis by 300 p.p.m. PhIP was observed. However, no prostate enhancement was demonstrated in the DMAB + PhIP group. Since PhIP-DNA adduct formation in the prostate epithelial cells in a satellite experiment was not affected by pre-treatment with DMAB, it is speculated that the contradictory findings between the intestine and prostate may be due to the specific biological effects of PhIP. Taking into account previous data, that PhIP clearly enhanced rat 1,2-dimethylhydrazine-initiated colon tumorigenesis, the potential of PhIP to enhance colon carcinogenesis may be initiator dependent.     

Mammary gland carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rats: possible mechanisms.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine derived from cooked meat. Mammary gland cancer can be induced in female Sprague-Dawley rats by administration of several oral doses of PhIP. The mechanism of mammary gland carcinogenesis by PhIP in this rat model is not fully understood but appears to involve several factors. One factor is the formation of PhIP-DNA adducts in the mammary gland after metabolic activation of PhIP. Possible target cell populations include the epithelial cells of the mammary gland terminal end buds (TEBs), putative sites of origin of carcinomas. Another factor involved in the mammary carcinogenicity of PhIP may be an increased proliferation in epithelial cells of the TEBs which occurs after a carcinogenic dose of PhIP is administered. This proliferation would be likely to enhance the fixation of mutations from PhIP-DNA adducts in target cells and facilitate the initiation of carcinogenesis. PhIP exposure also transiently inhibits the development of the mammary gland by retarding the differentiation of TEBs to alveolar buds and lobules. As a consequence, more TEBs are available for neoplastic transformation. Recent studies in rats have also shown that PhIP increases the levels of serum prolactin, a well-recognized promoter of mammary gland cancer, which may further explain the targeting of PhIP to the mammary gland. The results to date indicate that PhIP has multiple effects on the mammary gland and hormone status in rats that could potentially play a role in its ability to induce mammary gland cancer.     

Beef tallow, but not perilla or corn oil, promotion of rat prostate and intestinal carcinogenesis by 3,2'-dimethyl-4-aminobiphenyl.

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) were investigated. Non-invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg / kg body weight of DMAB at 2-week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non-carcinogen-treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P < 0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMA + TP (from 70 to 10%, P < 0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5-bromo-2-deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow.     

Beef Tallow, but Not Perilla or Corn Oil, Promotion of Rat Prostate and Intestinal Carcinogenesis by 3,2-Dimethyl-4-aminobiphenyl

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2-dimethyl-4-aminobiphenyl (DMAB) were investigated. Non-invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg/kg body weight of DMAB at 2-week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non-carcinogen-treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P<0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMAB + TP (from 70 to 10%, P<0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5-bromo-2-deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow.     

Dose Dependence of N-Hydroxy-3,2'-dimethyM-aminobiphenyl-induced Rat Prostate Carcinogenesis

Groups of F344 rats were administered biweekly intraperitoneal injections of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl (N-OH-DMAB) at a dose of 5, 10 or 20 mg/kg body weight or DMAB, the parent compound, at a dose of 25 mg/kg body weight, for a total of 10 times. Prostate carcinomas in the ventral lobe developed in a N-OH-DMAB dose-dependent manner (0, 17.6 and 66.7%, respectively) with limited tumor yields in other organs. Although intraperitoneal administration of DMAB was similarly found to induce prostate tumors, it also caused severe chemical peritonitis, which resulted in a high mortality. The present data confirmed that intraperitoneal administration of N-OH-DMAB provides a relatively specific induction method for models of prostate carcinogenesis.     

Dose dependence of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis.

Groups of F344 rats were administered biweekly intraperitoneal injections of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl (N-OH-DMAB) at a dose of 5, 10 or 20 mg/kg body weight or DMAB, the parent compound, at a dose of 25 mg/kg body weight, for a total of 10 times. Prostate carcinomas in the ventral lobe developed in a N-OH-DMAB dose-dependent manner (0, 17.6 and 66.7%, respectively) with limited tumor yields in other organs. Although intraperitoneal administration of DMAB was similarly found to induce prostate tumors, it also caused severe chemical peritonitis, which resulted in a high mortality. The present data confirmed that intraperitoneal administration of N-OH-DMAB provides a relatively specific induction method for models of prostate carcinogenesis.     

Decrease of Prostaglandin E2 and 5–Bromo–2'–deoxyuridine Labeling but Not Prostate Tumor Development by Indomethacin Treatment of Rats Given 3,2'–Dimethyl-4-aminobiphenyl and Testosterone Propionate

The modifying effects of indomethacin (IM) on rat prostate carcinogenesis induced by 3,2'–dimethyl–4–aminobiphenyl (DMAB) were investigated. F344 rats were given 50 mg/kg body weight of DMAB at 2–week intervals for 20 weeks and then received IM at a dose of 20 ppm in the drinking water for 37 weeks. Separate groups additionally received testosterone propionate (TP) in Silastic tubes throughout the experiment. DMAB alone induced carcinomas in situ in the ventral lobe and in combination with TP caused invasive carcinomas of the dorso–lateral and anterior lobes and seminal vesicles. No clear suppression by IM of development of in situ carcinomas or in vasive carcinomas was observed. In a short–term satellite experiment, it was revealed that prostaglandin E₂ (PGE₂) levels in the dorso–lateral prostate and seminal vesicles, but not the ventral prostate, were significantly reduced by IM and that TP itself also suppressed PGE₂ levels. The 5–bromo–2'–deoxyuridine labeling index in the ventral prostate was significantly decreased by IM administration. These results indicate that while IM can efficiently suppress tissue PGE₂ levels, it does not inhibit tumor development in the prostate or seminal vesicles of rats in the present model.     

Lobe specific effects of testosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis

We have previously shown that chronic administration of a pharmacological dose of testosterone propionate (TP) after treatment with the carcinogen, 3,2'-dimethyl-4-aminobiphenyl (DMAB), results in development of invasive and metastatic adenocarcinomas arising from the dorso-lateral and anterior prostate, as well as the seminal vesicles. Co-administration of ethinyl estradiol (EE) with TP increased the yield of carcinomas in the lateral and anterior lobes. In the present experiment, male F344 rats were treated with DMAB for 20 weeks and then co-administered a pharmacological dose of TP together with various doses of EE for 40 weeks. Without hormone(s) administration, carcinomas were confined to the ventral prostate and all were of intra-acinar type. TP administration suppressed development of the ventral prostate carcinomas but caused invasive carcinomas of the lateral and anterior lobes and of seminal vesicles and intra-acinar carcinomas in the dorsal prostate. The appearance of carcinomas in the lateral and anterior prostate was increased by co-administration of EE in a dose-related fashion but carcinomas of the seminal vesicles were inversely reduced. The suppressive influence of TP on ventral carcinoma development was overcome by only the highest dose of EE. It is concluded that estrogen can modify the enhancing effects of TP on induction of rat prostate and seminal vesicle carcinomas in a dose-related fashion with lobe specificity.     

Rapid induction of colon carcinogenesis in CYP1A-humanized mice by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine produced during the cooking of meats and fish, is suspected to be a human carcinogen. Metabolic activation of PhIP is primarily mediated by the enzyme cytochrome P450 (CYP) 1A2. Metabolism of PhIP by CYP1A2 differs considerably between humans and rodents, with more N(2)-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans. Transgenic CYP1A-humanized mice (hCYP1A-mice), which have the human CYP1A1 and CYP1A2 genes but lack the murine orthologs Cyp1a1 and Cyp1a2, provide an excellent opportunity to develop a relevant model to study dietary-induced colon carcinogenesis. The treatment with 200 mg/kg PhIP by oral gavage, followed by 1.5% dextran sodium sulfate (DSS) in the drinking water for 7 days, was found to be an effective combination to induce colon carcinogenesis in hCYP1A-mice. Tumor multiplicity at week 6 was calculated to be 3.75 ± 0.70 and for week 10 was 3.90 ± 0.61 with 80-95% of the tumors being adenocarcinomas. No tumors were found in the similarly treated wild-type mice. Western blots revealed overexpression of β-catenin, c-Myc, cyclin D1, inducible nitric oxide synthase and cyclooxygenase-2 in colon tumor samples. Strong nuclear localization of β-catenin was observed in tumors. These results illustrate that PhIP and DSS combination produces rapid colon carcinogenesis in hCYP1A-mice and this is an effective model to mimic human colon carcinogenesis.     

Apocynin,an NADPH oxidase inhibitor,suppresses rat prostate carcinogenesis

Recent evidence suggests that oxidative stress contributes to the pathogenesis of prostate cancer. The present study focused on the effect of apocynin, an inhibitor of NADPH oxidase, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model. There were no toxic effects with apocynin treatment. The percentages and numbers of carcinomas in both the ventral and lateral prostate were significantly reduced by apocynin treatment, with dose dependence. Reduction of reactive oxygen species by apocynin was confirmed by immunohistochemistry of 8‐OHdG and dihydroethidium staining. Positivity of Ki67 was significantly reduced by apocynin treatment, and downregulation of clusterin expression, as well as inactivation of the MEK‐ERK1/2 pathway, was a feature of the apocynin treated groups. In human prostate cancer cell line LNCaP, apocynin also inhibited reactive oxygen species production and blocked cell growth by inducing G0/G1 arrest with downregulation of clusterin and cyclin D1. These data suggest that apocynin possesses chemopreventive potential against prostate cancer.     

Suppressive effects of dietary genistin and daidzin on rat prostate carcinogenesis.

High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and / or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P < 0.05), with a tendency for decrease in incidence. Invasive carcinomas which developed in the anterior prostate and seminal vesicles with TP were, however, not influenced by the two isoflavones. Thus, the present data suggest that genistin and daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epidemiological findings.     

Suppressive Effects of Dietary Genistin and Daidzin on Rat Prostate Carcinogenesis

High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and/or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P<0.05), with a tendency for decrease in incidence. Invasive carcinomas which developed in the anterior prostate and seminal vesicles with TP were, however, not influenced by the two isoflavones. Thus, the present data suggest that genistin and daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epide-miological findings.     

Protection by chlorophyllin and indole-3-carbinol against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced DNA adducts and colonic aberrant crypts in the F344 rat

The most abundant heterocyclic amine in fried ground beef, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP), induces colon carcinomas in the male F344 rat. The potentialchemopreventive effects of two compounds, namely, the ‘interceptormolecule’ chlorophyllin (CHL) and a modulator of carcinogenactivation, indole-3-carbinol (I3C), were examined in a PhIPcolon carcinogenesis model. During weeks 3 and 4 of a 16-weekstudy, F344 rats were given PhIP by oral gavage (50 mg/kg bodyweight, alternating days). Inhibitors were given either beforeand during PhIP exposure, after PhIP treatment, or continuouslyfor 16 weeks. Treatment of rats with 0.1% CHL in the drinkingwater inhibited the formation of aberrant crypt foci (ACF) with