zanoterone and bicalutamide

The effect of the steroidal androgen receptor antagonist Win 49,596 on the prostate and testis was studied in beagle dogs and was compared to the effects of the nonsteroidal androgen receptor antagonist ICI 176,334 and the steroidal 5 alpha-reductase inhibitor MK-906. Win 49,596 was shown to bind to the androgen receptor from normal canine prostate with a Ki of 2.2 microM. After 16 weeks of treatment, prostate size, as estimated by transrectal ultrasonography, was unchanged in intact controls and was 26% of the initial size in castrate controls. Oral doses of Win 49,596 from 0.625-40 mg/kg.day for 16 weeks caused dose-dependent prostatic regression and a dose-related increase in both the incidence and severity of glandular atrophy of the prostate. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at 40 mg/kg.day on prostatic weight, total DNA, histomorphology, and secretory function were similar to those of castration, while the effects of Win 49,596 at 10 mg/kg.day were similar to those of ICI 176,334 at 0.25 mg/kg.day and MK-906 at 1.0 mg/kg.day. No effects on testicular weight, daily sperm production, or spermatogenesis were observed; however, mild Leydig cell hyperplasia was observed in two dogs treated with 40 mg/kg.day Win 49,596. In addition, at 10 and 40 mg/kg.day Win 49,596, moderate but variable increases in serum testosterone levels were observed. In summary, Win 49,596 caused regression of the hypertrophic canine prostate without effects on spermatogenesis and/or sexual function, supporting its possible use in the treatment of human benign prostatic hypertrophy/hyperplasia.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Androstenes; Anilides; Animals; Azasteroids; DNA; Dogs; Finasteride; Hypertrophy; Male; Nitriles; Orchiectomy; Organ Size; Pregnanes; Prostate; Prostatic Hyperplasia; Pyrazoles; Receptors, Androgen; Semen; Spermatogenesis; Testis; Testosterone; Tosyl Compounds; Ultrasonography

A series of experiments were conducted to investigate the regulation of the primary secretory protein of the canine prostate, arginine esterase, by androgens and/or new antiandrogen under development. In the first experiment, castration decreased (P less than 0.05) prostatic arginine esterase levels relative to intact controls (0.26 +/- 0.1 and 17.0 +/- 0.1 mumole/min/mg protein, respectively). Treatment of castrate dogs with either 5, 10, or 20 silastic capsules (8 cm length) containing the androgen 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) plus 1 capsule containing estradiol-17 beta (E2) or the i.m. injection of 25 mg 3 alpha-diol and 0.25 mg E2 for 12 weeks resulted in a dose-dependent increase (P less than 0.05) in prostatic arginine esterase activity (6.8 +/- 1.7, 19.0 +/- 3.6, 21.3 +/- 0.9, and 14.2 +/- 0.7 mumole/min/mg protein, respectively). In the second experiment, steroid treatment (10 3 alpha-diol plus 1 E2 silastic capsules) of castrate dogs for 12 weeks resulted in prostatic arginine esterase activity of 17.8 +/- 2.3 mu mole/min/mg. Co-administration of the steroidal androgen receptor antagonist. Win 49,596 (WIN) at doses of 0.625, 2.5, 10, or 40 mg/kg/day p.o., dose-dependently inhibited (P less than 0.05) prostatic arginine esterase activity (14.9 +/- 1.1, 14.3 +/- 1.3, 3.4 +/- 1.9, and 0.21 +/- 0.1 mumole/min/mg, respectively) to levels similar to that observed in castrate controls (0.14 +/- 0.03 mumole/min/mg). Administration of the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day p.o. to steroid-induced dogs also inhibited (P less than 0.05) arginine esterase activity (0.07 +/- 0.02 mumole/min/mg). In the last experiment, treatment of intact dogs with WIN at 0.625, 2.5, 10, and 40 mg/kg/day for 16 weeks dose-dependently reduced (P less than 0.05) arginine esterase levels (17.0 +/- 1.0, 16.3 +/- 1.5, 10.2 +/- 1.2, and 3.9 +/- 2.5 mumole/min/mg, respectively) compared to intact controls (14.4 +/- 1.2 mumole/min/mg). Histomorphologic and ultrastructural evaluation of prostates from dogs indicated that antiandrogen treatment resulted in glandular epithelial atrophy as well as a reduction in the number of secretory granules. The results of these experiments support that canine prostatic arginine esterase activity is under androgenic control, can be inhibited by antiandrogen treatment and may serve as a functional marker of the androgenic state of the prostate. Whether the effects of androgen and antiandrogen

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Androgens; Androstane-3,17-diol; Androstenes; Anilides; Animals; Azasteroids; Capsules; Carboxylic Ester Hydrolases; Dogs; Dose-Response Relationship, Drug; Estradiol; Finasteride; Flutamide; Hyperplasia; Injections, Intramuscular; Male; Nitriles; Pregnanes; Prostate; Prostatectomy; Pyrazoles; Tosyl Compounds

Win 49596 is a new orally active, steroidal androgen receptor antagonist. Win 49596 inhibited ventral prostate, seminal vesicle and levator ani weight gain in either 5 alpha-dihydrotestosterone (DHT) or testosterone propionate-treated castrated, immature male rats. In intact, adult male rats, Win 49596 significantly inhibited weight gain by the ventral prostate, dorsal lateral prostate and seminal vesicles, but not the testes at doses as low as 50 mg/kg/day x 14 p.o. However, daily oral administration of equivalent antiandrogenic doses of either Win 49596, ICI 176,334, or flutamide for 14 days to mature, intact male rats resulted in elevations of circulating testosterone of approximately 3-, 2-, and 10-fold, respectively. At doses as high as 400 mg/kg p.o., Win 49596 did not have androgenic, progestational, estrogenic or antiestrogenic activity in rat or rabbit models. However, in the Clauberg assay, Win 49596 did have weak antiprogestational activity at doses of 25-400 mg/kg/day p.o. These data indicate that Win 49596 is a peripherally selective antiandrogen that has minimal effects on circulating testosterone levels and is devoid of hormone agonist activity. Thus, Win 49596 may be useful for the treatment of androgen dependent conditions such as benign prostatic hyperplasia and prostatic cancer.

Topics: Androgen Receptor Antagonists; Anilides; Animals; Estrogen Antagonists; Female; Flutamide; Genitalia, Male; Male; Nitriles; Orchiectomy; Pregnanes; Progesterone; Pyrazoles; Rabbits; Rats; Rats, Inbred Strains; Testosterone; Tosyl Compounds