Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice

Development of effective chemopreventive agents for human consumption requi res conclusive evidence of their efficacy in animal models that have releva nce to human diseases. Transgenic adenocarcinoma mouse prostate (TRAMP) is an excellent model of prostate cancer that mimics progressive forms of huma n disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-2 8 weeks of age. In these animals, ornithine decarboxylase (ODC) activity (> 3-fold) as well as protein expression (>4-fold) was found to be markedly hi gher in the dorsolateral prostate as compared with the nontransgenic litter mates, suggesting their suitability to determine the chemopreventive effect of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, against prostate cancer, Using male TRAMP mice, we studie d the effect of oral consumption of DFMO on development of prostate carcino genesis and surrogate end point biomarkers related to prostate cancer progr ession, In two independent experiments, each consisting of 8 animals on tes t, the cumulative incidence of prostatic cancer development at 28 weeks of age in 16 untreated TRAMP mice was 100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the animals exhibited distant site metastases to lymp h nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the d rinking water to TRAMP mice from 8 to 28 weeks of age resulted in a signifi cant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitou rinary weight (63%), and (c) ODC enzyme activity (52%) in the dorsolateral prostate. Importantly, in none of the DFMO-fed TRAMP mice were any distant metastases to lymph node and lungs observed. Furthermore, DFMO treatment re sulted in the marked reduction in the protein expression of proliferation c ell nuclear antigen, ODC, and probasin in the dorsolateral prostate. The pr otein expression of antimetastases markers, i.e,, E-cadherin and alpha- and beta-catenin, was found to be restored in DFMO-fed animals as compared wit h the non-DFMO-fed mice, These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Hi stological analysis of the dorsolateral prostate of DFMO-fed animals displa yed marginal epithelial stratification, a small number of cribriform struct ures, elongated hyperchromatic epithelial nuclei, and a significant increas e in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed ex tensive epithelial stratification with profound cribriform structures accom panied with marked thickening, remodeling, and hypercellularity of the fibr omuscular stroma, In nontransgenic littermates fed with DFMO, no significan t alterations in the above parameters were evident. These data demonstrate that ODC represents a promising and rational target for chemoprevention of human prostate cancer and that TRAMP mice are excellent models for screenin g of novel drugs and chemopreventive regimens for potential human use.