Induction of prostatic carcinomas and lower urinary tract neoplasms by combined treatment of intact and castrated rats with testosterone propionate and N-nitrosobis(2-oxopropyl)amine

Abstract

The effect of exogenous testosterone on prostatic carcinogenicity of N-nitrosobis(2-oxopropyl)amine (BOP) in intact and castrated rats was examined in Wistar-derived MRC rats. Daily administration of BOP (either s.c. or i.g.) for 3 days, at a dose of 20 mg/kg b.w. at the heights of prostatic cell proliferation induced by testosterone, led to development of a large number of prostatic tumors, the incidence of which, however, was dependent on the duration of testosterone administration. Testosterone given for life following BOP administration induced prostatic cancer in over 60% of rats, regardless of whether BOP was given orally or s.c., or whether the rats were orchiectomized or not, whereas tumor incidence was significantly lower in rats treated with testosterone for only a short period of time. One (3%) orchiectomized rat, which received testosterone only during BOP treatment, and four (15%) of rats treated with testosterone only for life also developed carcinomas. Histologically, a large number of BOP + testosterone-induced prostatic tumors were adenocarcinomas of various histological patterns and arose primarily from the dorsal lobe, whereas the great majority of squamous cell carcinomas were found in the ventral lobe. Simultaneously induced tumors were papillomas and carcinomas of the urinary bladder and urethra. Testosterone appeared to enhance the incidence of urinary bladder tumors, but not of the urethral tumors, whereas orchiectomy inhibited urethral carcinogenesis, and, to much lesser extent, urinary bladder tumor development. Rats treated weekly for 20 weeks with BOP (10 mg/kg/week i.g.) did not develop any prostatic tumors and all rats died of rectal cancer. Of rats treated similarly with BOP and with testosterone pellets for life following the last injection of BOP, 17% of rats developed prostatic cancer, all of the squamous cell type. Simultaneous testosterone and BOP treatment for 20 weeks followed by testosterone pellets for life resulted in a 39% tumor incidence (three adenocarcinomas, one anaplastic carcinoma, and five squamous cell carcinomas). The overall results suggest that testosterone plays an important role in the initiation of prostatic carcinogenesis, whereas the promotional phase is governed by the interaction of testosterone with other factors.