Inhibition of tumor development in the regenerating rat urinary bladder stimulated to proliferate by cyclophosphamide.

The present study deals with the effect of stimulation of urothelial proliferation on experimental bladder carcinogenesis. To induce proliferative activity of the bladder mucosa cyclophosphamide (cp) was intraperitoneally administered to rats in a single dose (100 mg/kg). N-Butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) was used as carcinogen and administered by gavage in 3 fractionated doses when proliferation of the urothelium was highest at 28 and 40 hr as well as 7 days following the injection of cp. Contrary to our original working hypothesis, tumor development proved to be inhibited in the bladder following initial stimulation of urothelial proliferation by cp. After administration of a low total dose of BBN (300 mg/kg) and an experimental period of 6 and 12 months none of the rats pretreated with cp developed a tumor in the regenerating bladder, whereas solitary transitional cell papillomas were observed in 6.7% of the control animals with a quiescent bladder. Following administration of BBN at a high total dose (1.300 mg/kg) and an induction time of 4, 6 and 12 months papillomas and non-invasive papillary transitional cell carcinomas occurred in only 21.6% of the rats initially receiving cp but in 48.1% of the control animals without stimulation of urothelial proliferation by cp. After treatment with BBN alone there was a far larger number of rats with multiple tumors in the quiescent bladder. The reduction in the incidence of tumors following administration of cp is not attributable to a prolongation of the latency period or induction time. It is an open question which mechanisms are responsible for the observed inhibition of experimental bladder carcinogenesis. An increased DNA repair induced synchronously with the stimulated replicative de-novo DNA synthesis or a decreased activity of urothelial enzymes metabolizing BBN to its ultimate carcinogen are proposed as the most likely explanations.