K.V.N. Rao

Chemoprevention of Hormone-Dependent Prostate Cancer in the Wistar-Unilever Rat

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

Null activity of selenium and vitamin e as cancer chemopreventive agents in the rat prostate.

To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were done in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At 1 week post-MNU, groups of carcinogen-treated rats (39-44/group) were fed either a basal diet or a basal diet supplemented with l-selenomethionine (3 or 1.5 mg/kg diet; study 1), dl-α-tocopherol (vitamin E, 4,000 or 2,000 mg/kg diet; study 2), l-selenomethionine + vitamin E (3 + 2,000 mg/kg diet or 3 + 500 mg/kg diet; study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), show the predictive nature of this animal model for human prostate cancer chemoprevention. Cancer Prev Res; 3(3); 381–92

Hamster Lung Cancer Model of Carcinogenesis and Chemoprevention

Attempts to establish a lung cancer model in hamsters that is histologically and biochemically similar to bronchogenic carcinoma in man have had limited success (1,2). Earlier hamster and mouse studies employed methods such as thread transfixions (3, 4) and exposure to radioactive compounds either by inhalation (5) or implantation of intrabronchial pellets (6). Lung cancer models in hamsters employed by Saffiotti and his associates (7–10) required the intratracheal instillation of suspensions of a crystalline polycyclic aromatic hydrocarbon adsorbed to carrier particles of inert dust. The use of nitroso-compounds, with and without carrier dust, to induce tracheal and pulmonary lesions in hamsters has also been employed (11–15). However, the physiochemical properties of these carcinogens, such as solubility and particle size, and the nature of the carrier particles are very critical with regard to tumor induction. As a result, the feasibility of obtaining a reproducible incidence of respiratory cancer in different laboratories using these techniques appears remote. Furthermore, many of the earlier lung tumor models exhibited a very low cancer incidence and a long latency period.