Development of effective chemopreventive agents for human consumption requires conclusive evidence of their efficacy in animal models that have relevance to human diseases. Transgenic
adenocarcinoma mouse prostate (TRAMP) is an excellent model of
prostate cancer that mimics progressive forms of human disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to
adenocarcinoma with distant site
metastases by 24-28 weeks of age. In these animals,
ornithine decarboxylase (ODC) activity (>3-fold) as well as
protein expression (>4-fold) was found to be markedly higher in the dorsolateral prostate as compared with the nontransgenic littermates, 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 studied the effect of oral consumption of DFMO on development of prostate
carcinogenesis and
surrogate end point biomarkers related to
prostate cancer progression. In two independent experiments, each consisting of 8 animals on test, 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 lymph nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the
drinking water to TRAMP mice from 8 to 28 weeks of age resulted in a significant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitourinary 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 resulted in the marked reduction in the
protein expression of proliferation cell
nuclear antigen, ODC, and
probasin in the dorsolateral prostate. The
protein expression of antimetastases markers, i.e.,
E-cadherin and alpha- and
beta-catenin, was found to be restored in DFMO-fed animals as compared with the non-DFMO-fed mice. These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Histological analysis of the dorsolateral prostate of DFMO-fed animals displayed marginal epithelial stratification, a small number of cribriform structures, elongated hyperchromatic epithelial nuclei, and a significant increase in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed extensive epithelial stratification with profound cribriform structures accompanied with marked thickening, remodeling, and hypercellularity of the fibromuscular stroma. In nontransgenic littermates fed with DFMO, no significant 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 screening of novel drugs and chemopreventive regimens for potential human use.