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Comparison of the Pharmacological Effects of a Novel Selective Androgen Receptor Modulator, the 5-Reductase Inhibitor Finasteride, and the Antiandrogen Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Hyperplasia

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University (W.G., J.D.K., J.T.D.), Columbus, Ohio 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee (V.A.N., D.D.M.), Memphis, Tennessee 38163; GTx, Inc. (K.C.), Memphis, Tennessee 38163; and National Hormone and Peptide Program, Harbor-University of California-Los Angeles Medical Center (A.F.P.), Torrance, California 90509

Address all correspondence and requests for reprints to: Dr. James T. Dalton, 500 West 12th Avenue, L. M. Parks Hall, Room 242, Columbus, Ohio 43210. E-mail: dalton.1{at}osu.edu.

Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5-reductase (K_i, >20 µM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.

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