Inhibition of steroid-induced prostatic hyperplasia in rats by treatment with anti-androgen (TZP-4238)

Abstract

The effect of a synthetic steroidal anti-androgen, TZP-4238, on steroid-induced rat prostatic hyperplasia was investigated. Male Wistar rats were divided into four experimental groups. Group 1 consisted of intact controls. The other animals were castrated. The castrated animals were treated for 7 weeks with 1) testosterone 1 mg/head plus 17 beta-estradiol (E2) 0.01 mg/head (Group 2), 2) testosterone plus E2 + TZP-4238 8 mg/kg (Group 3) and 3) testosterone plus E2 + chlormadinone acetate (CMA) 20 mg/kg (Group 4). TZP-4238 and CMA were administered orally for 4 weeks after 3 weeks treatment with testosterone plus E2. In group 2, glandular hyperplasia of the prostate was clearly observed, and the number of bromo-deoxyuridine (BrdU)-positive cells showed a significant increase. In contrast, combined treatment with TZP-4238 (Group 3) or CMA (Group 4) produced marked atrophy of the glandular epithelium, and the number of BrdU-positive cells were remarkably decreased compared with Group 2. In addition, the localization of glutathione-peroxidase (GSH-PO) which effectively reduces the lipid peroxides in the glandular epithelial cells was markedly decreased. Furthermore, nuclear immunostaining of androgen receptor was remarkably decreased after combined treatment with TZP-4238 or CMA. Our data indicate that TZP-4238 is a potent steroidal androgen receptor antagonist for the prevention of rat prostatic growth in the steroid-induced prostatic hyperplasia model.