Modification of N-methyl-N-nitrosourea-induced urinary bladder carcinogenesis in rats following stimulation of urothelial proliferation by a partial cystectomy

Abstract

The present experiments are concerned with the question whether stimulation of urothelial proliferation modifies tumor development in the urinary bladder. To induce proliferative activity of the urothelium a partial cystectomy (one-third resection of the bladder) was performed in female Wistar rats. N-Methyl-N-nitrosourea (MNU) was used as a carcinogen which acts directly on the urothelium without requiring metabolic activation. MNU was given as a single intravesicular dose of 5 mg/kg body weight via a urethral catheter. After an experimental period of 15 months rats with an intact quiescent bladder showed a tumor incidence of 32.6%. Rats having received MNU 45 h following partial cystectomy — when proliferative activity reached its peak — had developed bladder tumors with a frequency of 17.9%. Initial administration of MNU followed 24 h later by a one-third resection of the bladder resulted in a tumor incidence of only 8.8%. The histologic types of tumors induced proved to be similar to those found with other carcinogens. However, by contrast the majority of urothelial tumors were characterized by a squamous metaplasia. There was no substantial difference between the various histologic tumor types found in the resting and regenerating bladder. The mechanisms responsible for the observed inhibition of tumor development in the regenerating bladder are unknown. It is assumed that an increased capacity of the proliferating urothelial cells to repair carcinogen-induced DNA damage may play an important role.