Inhibition of tumour development in the partially resected, proliferating rat urinary bladder.

Abstract

Autoradiographic studies have shown that the urothelium of the rat urinary bladder is capable to considerably proliferate in response to a partial cystectomy (one-third resection of the bladder) as is indicated by a 190-fold increase of the 3H-thymidine labelling index above normal levels 45 h postoperatively and an enormous increase of the compartment of proliferating cells (so-called growth fraction). The stimulated urothelial proliferation can be synchronized by multiple, fractionated doses of hydroxyurea (HU), resulting in a high degree of synchrony. Based on these findings, the partial cystectomy model seemed to be a useful tool to examine whether stimulated proliferation exerts a modifying effect on initiation of urothelial carcinogenesis. Following feeding N-butyl-N-(4-hydroxybutyl)-nitrosamine by gavage in 3 fractionated doses during most pronounced proliferation 30, 45 and 70 h postoperatively, the development of bladder tumors proved to be significantly dose- and time-related inhibited. Accordingly, N-methyl-N-nitrosourea (MNU)-induced tumour formation was considerably reduced following intravesicular instillation of the carcinogen at a single dose 45 h postoperatively, when stimulated DNA synthesis reached its peak. Experiments testing a possible cell cycle specific dependence of MNU-initiated tumor development in the partially resected bladder after synchronization of the stimulated proliferation by HU revealed an inhibition of urothelial carcinogenesis in particular, when the carcinogen was administered during the early DNA synthesis phase. The mechanisms underlying the observed inhibition of tumor development in the regeneration urinary 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.