Inhibition of steroid-induced prostatic hyperplasia in rats by treatment with anti-androgen (TZP-4238).
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.
Murakoshi
M
M
Safety Research Department, Teikoku Hormone Mfg. Co. Ltd., Kawasaki, Japan.
Tagawa
M
M
Inada
R
R
Suzuki
M
M
Mizokami
A
A
Watanabe
K
K
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002715:Chlormadinone Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology
D000726:Androgen Antagonists; D011944:Receptors, Androgen; D002715:Chlormadinone Acetate; D013739:Testosterone; D004958:Estradiol; D005979:Glutathione Peroxidase; C069297:osaterone acetate; D001973:Bromodeoxyuridine