EFFECT OF COMBINATION TREATMENT WITH ZANOTERONE (WIN-49596), A STEROIDAL ANDROGEN RECEPTOR ANTAGONIST, AND FINASTERIDE (MK-906), A STEROIDAL 5-ALPHA-REDUCTASE INHIBITOR, ON THE PROSTATE AND TESTES OF BEAGLE DOGS

The effects of the steroidal androgen receptor antagonist zanoterone ( WIN 49596) and the steroidal 5alpha-reductase inhibitor finasteride (M K-WIN 906) either alone or in combination on prostatic size, histomorp hology, and biochemistry were determined in the intact male dog. Addit ionally, the effects of treatment with zanoterone and/or finasteride o n testicular size, serum testosterone and LH levels, and spermatogenes is were determined in the same dogs. Daily oral treatment for 16 weeks with either zanoterone alone at 10 mg/kg.day or finasteride alone at 1.0 mg/kg . day reduced (P < 0.05) the size of the prostate, resulted in mild to moderate diffuse glandular atrophy of the prostate, and dec reased prostatic DNA and prostatic arginine esterase (the primary cani ne prostatic protein) levels compared to those in intact controls. The se changes occurred with no effect on testicular weight, testicular hi stomorphology, daily sperm production, or serum LH levels. Serum testo sterone concentrations were increased (P < 0.05) approximately 3-fold in the 10 mg/kg.day zanoterone treatment group compared to those in in tact controls. Combination treatment of male dogs for 16 weeks with za noterone (10 mg/kg.day) plus finasteride (1.0 mg/kg. day) orally also reduced (P < 0.05) prostate size, resulted in moderate to marked diffu se prostatic glandular atrophy, and decreased prostatic DNA and argini ne esterase levels more than either drug alone, without affecting test icular size, testicular histomorphology, serum LH concentrations, or s erum testosterone concentrations compared to those in intact controls. The effects of combination treatment with zanoterone and finasteride on prostatic size; histomorphology; and DNA, arginine esterase protein , and arginine esterase mRNA levels were similar to those observed in castrate controls. In addition, in situ estimates of prostatic size us ing transrectal ultrasonography indicated that the median time to 70% prostatic regression in dogs administered combination zanoterone plus finasteride was similar to that in castrate controls (9.6 and 9.3 week s, respectively), indicating that the combination was more effective i n causing prostatic regression than either drug alone. Finally, at the dosages used, no adverse effects of combination treatment with zanote rone plus finasteride on testicular or other major body organ weights were observed. Based on these results, combination therapy using zanot erone and finasteride for the treatment of human androgen-dependent di sorders such as benign prostatic hyperplasia and prostate cancer has p otential utility.