Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice.

Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), ß-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer.

High-dose dietary zinc promotes prostate intraepithelial neoplasia in a murine tumor induction model.

To evaluate the role of high-dose dietary zinc in the process of prostate malignancy, 60 Sprague-Dawley rats were randomly divided into four groups: tumor induction with carcinogen and hormone (group 1), oral zinc administration without tumor induction (group 2), oral zinc administration with tumor induction (group 3) and a control without zinc administration or tumor induction (group 4). Zinc was supplied orally in the form of zinc sulfate heptahydrate dissolved in drinking water to groups 2 and 3 for 20 weeks. Although the serum level of zinc measured at 20 weeks was maintained similarly in each group (P = 0.082), intraprostatic zinc concentrations were statistically different. Group 1 prostates contained the least amount of zinc in both the dorsolateral and ventral lobes at levels of 36.3 and 4.8 microg g(-1), respectively. However, in group 3, zinc levels increased in both lobes to 59.3 and 12.1 microg g(-1), respectively, comparable with that of group 4 (54.5 +/- 14.6 and 14.1 +/- 2.4 microg g(-1)). In spite of these increases in zinc concentration, the prevalence of prostate intraepithelial neoplasm was rather increased in group 3 (53.3% and 46.7%) compared with group 1 (33.3% and 33.3%) in both dorsolateral and ventral prostate lobes. Although prostate intraepithelial neoplasm did not develop in any prostate in group 4, zinc administration did induce prostate intraepithelial neoplasm in group 2 (46.7% and 40.0%). Thus, although high dietary zinc increased intraprostatic zinc concentrations, it promoted, instead of preventing, prostate intraepithelial neoplasm in a murine prostate malignancy induction model.

Prostate intraepithelial neoplasia in Noble rats, a potential intermediate endpoint for chemoprevention studies.

In most prostate chemoprevention studies conducted with animal models, the incidence and multiplicity of tumours have been used as endpoints for efficacy. However, the latency of tumours is usually over 1 year, making these studies costly and time consuming. The main purpose of this study was to assess the utility of prostate intraepithelial neoplasia (PIN), induced in Noble rats by continuous testosterone + oestradiol (T + E) administration, as a potential intermediate endpoint biomarker of efficacy in chemoprevention studies. Noble rats at the age of 12 weeks were treated for 36 weeks with T + E given subcutaneously via Silastic capsules. The incidence and multiplicity of PIN were assessed in various prostate glands by serial sections generated at three separate tissue levels. The efficacy of dehydroepiandrosterone (DHEA) and DHEA 8354 (1000 and 2000 mg/kg diet), difluoromethylornithine (DFMO) (1000 and 2000 mg/kg diet) and oltipraz (125 and 250 mg/kg diet) to inhibit PIN was assessed in two independent sets of experiments. T + E induced multiple PIN in the dorsolateral prostate (DLP) of 80-100% of the animals. DHEA and DHEA 8354 did not affect the incidence but decreased the multiplicity of PIN in the DLP, from 3.2 +/- 1.0 in control group to 1.5 +/- 1.0 in the low-dose and to 1.6 +/- 0.6 in the high-dose group for DHEA (P<0.05 and P<0.02, respectively), and to 1.9 +/- 0.8 in the high-dose (P<0.05) DHEA 8354. Both agents did not affect PIN in anterior prostate, seminal vesicles or ventral prostate. In a second experiment, DFMO and oltipraz were found not effective in inhibiting PIN. In this study, we provide new evidence that PIN in Noble rats, induced by continuous T + E treatment, is a useful intermediate endpoint for determining the efficacy of DHEA and other potential chemopreventive agents. The hormonal pathogenesis, high multiplicity, short latency, preferential location in the DLP, similarity in morphology and biology to PIN of human prostate, and the sensitivity to agents that suppress prostate carcinogenesis, makes PIN in Noble rats a promising intermediate endpoint for chemoprevention studies.