Use of animal models in defining efficacy of chemoprevention agents against prostate cancer

Animal models are crucial in preclinical efficacy testing of chemopreventio n agents. The most feasible, realistic, and potentially effective target fo r prostate cancer chemoprevention is progression from prostatic intraepithe lial neoplasia (PIN) to histologic cancer and from histologic to clinically manifest cancer. There are transgenic mouse models for prostate cancer and models for PIN, but these have not yet been fully developed and evaluated for chemoprevention studies. Human prostate cancer xenografts in mice and t ransplantable Dunning rat prostate carcinomas can be used to assess tumor g rowth inhibition. Several Dunning tumors metastasize, enabling detection of inhibition of metastases. Detection of inhibitory effects on de novo prost ate cancer development requires induction of a high cancer incidence and si milarity of induced tumors to human prostate carcinomas. Transgenic mice wi th oncogenes expressed in a prostate-specific fashion, combined chronic tre atment of NBL rats with estradiol-17 beta and testosterone, and sequential treatment of rats with carcinogens such as N-methyl-N-nitrosourea (MNU) and chronic testosterone treatment all lead to a high incidence of prostatic a denocarcinomas. PIN occurs mostly in the former two models, and metastases are frequent in some transgenic models and the MNU-testosterone rat model. The latter model has been applied to chemoprevention agent efficacy testing . In 8 control groups, the carcinoma incidence was 77% in all accessory sex glands combined, 51% for small tumors confined to dorsolateral/anterior pr ostate, and 25% for large tumors of uncertain origin in the prostate area. This model was predictive of the lack of antiprostate cancer efficacy of N- (4-hydroxyphenyl)all-trans-retinamide in humans. Thus, rats given MNU and c hronic testosterone represent a relevant and reliable model for efficacy te sting of chemoprevention agents. In conclusion, there are now adequate anim al models for prostate cancer proven to be suitable for preclinical chemopr evention studies.