Cell cycle dependence of N-methyl-N-nitrosourea-induced tumour development in the proliferating, partially resected...

In the present experiments the dependence of tumour induction upon the different phases of the cell cycle in the proliferating urinary bladder was examined. For stimulation of urothelial proliferation, a one-third resection of the bladder was performed in female Wistar rats. To synchronize the proliferating urothelial cells, hydroxyurea (HU) was given in 23 fractionated, consecutive intraperitoneal doses (0.1 mg/g body weight each) at hourly intervals shortly prior to and during maximal proliferation (between 33 and 55 h following partial cystectomy). The direct-acting urothelial carcinogen N-methyl-N-nitrosourea (MNU) was administered as a single, intravesicular pulse dose (5 mg/kg body weight) during the different cell cycle phases and to control animals with a non-resected, quiescent bladder (G0-phase). The incidence of urothelial bladder tumours was 32.6% in the controls. By comparison, the tumour incidences were 18.9, 9.3, 21.7, 26.3, 25.0 and 30.0%, respectively, when MNU was instilled during the late G1-, early and late S-, G2 + M-, and the early and late postmitotic phase. The results obtained from a total of 283 rats thus clearly document a cell-cycle-specific inhibition of MNU-induced tumour development in the proliferating urinary bladder, particularly when the carcinogen was administered during the early S-phase (P less than 0.016). There were no differences in the histology and extension of the urothelial bladder tumours found in the different experimental groups. MNU has also been shown to produce urothelial tumours in the renal pelvis (overall tumour incidence: 3.2%) and ureters (1.4%) as well as mesenchymal tumours in the bladder (4.9%) and kidneys (1.4%). Conclusions are tentatively drawn about the mechanisms underlying the observed cell-cycle-specific inhibition of urothelial carcinogenesis.