Carcinogenesis Advance Access originally published online on September 3, 2006
Carcinogenesis 2007 28(2):398-403; doi:10.1093/carcin/bgl141
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Chemoprevention of rat prostate carcinogenesis by dietary 16
-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone
1 Life Sciences Group, IIT Research Institute Chicago, IL 60616, USA
2 Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute Bethesda, MD 20892, USA
3 Department of Environmental Medicine and Urology, New York University School of Medicine New York, NY 10016, USA
*To whom correspondence should be addressed at: IIT Research Institute, 10 West 35th Street, Chicago, IL 60616, USA. Tel: +1 312 567 4972; Fax: +1 312 567 4021; Email: dmccormick{at}iitri.org
Dehydroepiandrosterone (DHEA) is a potent inhibitor of prostate carcinogenesis in rats. However, concerns related to the possible androgenicity of DHEA may preclude its use for chemoprevention of human prostate cancer. Studies were performed to compare the androgenicity of DHEA and a fluorinated DHEA analog, 16
-fluoro-5-androsten-17-one (fluasterone), and to determine the chemopreventive activity of fluasterone in the rat prostate. Comparisons of accessory sex gland weight and histology in gonadectomized male rats demonstrated that fluasterone is less androgenic than is DHEA. Fluasterone conferred significant protection against prostate carcinogenesis induced in Wistar-Unilever rats by a sequential regimen of N-methyl-N-nitrosourea + testosterone. Chronic administration of fluasterone at levels of 2000 and 1000 mg/kg diet reduced the incidence of adenocarcinoma in the dorsolateral/anterior prostate from 64% in dietary controls to 28 and 31%, respectively. Other than a dose-related suppression of body weight gain, chronic exposure to fluasterone induced no clinical evidence of toxicity; suppression of body weight gain may be either a pharmacological effect or a minimally toxic effect of the compound. These data demonstrate that a minimally androgenic analog of DHEA protects against prostate carcinogenesis induced in rats by a chemical carcinogen + androgen. The reduced androgenicity of fluasterone may obviate toxicities associated with the androgenicity of the parent compound. On this basis, fluasterone merits consideration for evaluation in clinical trials for prostate cancer prevention. The chemopreventive activity of a non-androgenic DHEA analog suggests that at least a portion of the chemopreventive activity of DHEA in the rat prostate is unrelated to hormonal effects.
Abbreviations: 11-HSD Type 1, 11-hydroxysteroid dehydrogenase type 1; DHEA, dehydroepiandrosterone; MNU, N-methyl-N-nitrosourea
Received May 2, 2006; revised July 11, 2006; accepted July 21, 2006.
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