Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat

The high incidence and long latent period of prostate cancer make it an ide al target for chemoprevention. We have evaluated a series of agents for che mopreventive efficacy using a model in which hormone-dependent prostate can cers are induced in the Wistar-Unilever (WU) rat by sequential treatment wi th antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone), This regimen reproducibly ind uces prostate cancers in high incidence, with no gross toxicity and a low i ncidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the mo st active agents identified to date. DHEA inhibits prostate cancer inductio n both when chronic administration is begun prior to carcinogen exposure, a nd when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis i dentified; a study to determine the efficacy of delayed administration of 9 -cis-RA is in progress. Liarozole fumarate confers modest protection agains t prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide ), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vi tamin E), and L-selenomethionine are inactive. Chemoprevention efficacy eva luations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.