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, 16alpha-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.