Development of N-butyl-N-(hydroxybutyl)-nitrosamine-induced tumors in the partially resected, proliferating rat urinary bladder in dependence upon the time of onset of stimulated DNA synthesis.

Tumor development was investigated in the partially resected, proliferating urinary bladder of rats in dependence upon the onset of stimulated de novo DNA synthesis related to carcinogen dosing. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) was used as carcinogen and administered by gavage in three fractionated doses (100 mg/kg body weight each) either during the phase of the most pronounced proliferation of the urothelium 30, 45 and 70 h after one-third resection of the bladder or 24 h and 1 week prior to partial cystectomy. When BBN was given during most increased DNA synthesis subsequent to one-third resection, the incidence of bladder tumors was reduced to 8.7% compared with 19.6% found in control animals with a non-resected, quiescent bladder. Tumor formation was neither inhibited nor enhanced when BBN was initially administered, followed by partial cystectomy 24 h or 1 week after the last carcinogen dose, yielding tumor incidences of 18.2% and 22.5%, respectively. Thus, the feeding of BBN during the period of maximum DNA synthesis inhibited tumor development in the partially resected bladder, while stimulation of cell replication subsequent to carcinogen administration did not influence the carcinogenic process initiated. The results obtained indicate that time of onset of stimulated DNA synthesis related to carcinogen dosing is the decisive factor in modifying urothelial carcinogenesis in the proliferating urinary bladder.