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Carcinogenesis Advance Access published online on September 3, 2006
Carcinogenesis, doi:10.1093/carcin/bgl141
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received May 2, 2006
Revised July 11, 2006
Accepted July 21, 2006

CANCER PREVENTION

Chemoprevention of rat prostate carcinogenesis by dietary 16{alpha}-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone

David L. McCormick 1 *, William D. Johnson 1, Nicole M. Kozub 1, K. V. N. Rao 1, Ronald A. Lubet 2, Vernon E. Steele 2, and Maarten C. Bosland 3

1 Life Sciences Group, IIT Research Institute, Chicago, Illinois 60616
2 Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892
3 Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016; Department of Urology, New York University School of Medicine, New York, New York 10016

* To whom correspondence should be addressed.
David L. McCormick, E-mail: dmccormick{at}iitri.org


  Abstract

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{alpha}-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 pharmacologic 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.

Keywords: chemoprevention; fluasterone; dehydroepiandrosterone analog; prostate cancer.
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