Promoting effects and mechanisms of action of androgen in bladder carcinogenesis in male rats.
OBJECTIVE
It has been reported that blocking of testosterone production inhibits bladder carcinogenesis in various animal models. We investigated how testosterone acts on rat bladder carcinogenesis using an antiandrogen, flutamide, and a 5 alpha-reductase inhibitor, finasteride.


METHODS
Experiment 1: we administered 0.05% BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine] orally to 117 Wistar rats for 10 weeks, divided them into seven groups-control, surgical castration, finasteride (2 mg/kg), luteinizing hormone releasing hormone (LH-RH) agonist (1 mg/kg) flutamide (50 mg/kg), LH-RH agonist plus finasteride, and LH-RH agonist plus flutamide-, and then cystectomized them to investigate the incidence of bladder cancer on week 21; experiment 2: we administered 0.05% BBN to 154 Wistar rats for 7 weeks, divided them into seven groups-control, finasteride 2, 4, and 8 mg/kg, and flutamide 50, 100, and 200 mg/kg-, and then we cystectomized them to investigate the dose-dependent influence on bladder carcinogenesis of these drugs on week 20, and experiment 3: we investigated the presence of androgen receptors in rat and mouse normal bladder mucosa using a monoclonal antibody.


CONCLUSIONS
Experiment 1: Surgical castration and LH-RH agonist treatment significantly reduced the occurrence of carcinomas. There was no significant additive effect of coadministered finasteride or flutamide with LH-RH agonist. Finasteride or flutamide monotherapy showed no statistically significant effects on the results of experiment 1 at the doses used. Experiment 2: Flutamide showed a dose-dependent effect on reducing the number of rats with bladder cancer, and at a dosis of 200 mg/kg twice a week, the difference was statistically significant when compared with the control group, whereas finasteride had no statistically significant suppressing effect at any dose. Experiment 3: Mouse and rat bladder urothelium expressed the androgen receptor. Our results indicate that testosterone itself might have a more potent action on bladder carcinogenesis rather than its converting form, 5 alpha-dihydrotestosterone.
Imada
S
S
Department of Urology, University of Tsukuba, Japan.
Akaza
H
H
Ami
Y
Y
Koiso
K
K
Ideyama
Y
Y
Takenaka
T
T
D000284:Administration, Oral; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D042944:Cholestenone 5 alpha-Reductase; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018120:Finasteride / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D007150:Immunohistochemistry; D016729:Leuprolide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D004791:Enzyme Inhibitors; D007987:Gonadotropin-Releasing Hormone; D002085:Butylhydroxybutylnitrosamine; D018120:Finasteride; D005485:Flutamide; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase; D016729:Leuprolide