Strong promoting activity of reversible uracil-induced urolithiasis on urinary bladder carcinogenesis in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The tumor-promoting effect of uracil-induced calculi on rat urinary bladder carcinogenesis was investigated in male F344 rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Since uracil-induced calculi and papillomatosis of the bladder are reversible, uracil was given for a limited period after the treatment with BBN. Animals were given 0.05% BBN in their drinking water for 4 wk and then treated with uracil as 3% of the diet for 8 or 16 wk. After the uracil treatment, rats were given basal diet without uracil until Wk 28 of the experiment. Animals were killed from each group at the end of either Wk 12, 20, or 28. The incidence of carcinoma of the bladder was 40% after only 8 wk of uracil treatment following BBN initiation and increased to 100% when uracil treatment was extended to 16 wk. After discontinuation of uracil treatment, the papillomatosis disappeared, but the incidence of carcinoma steadily increased with increasing time. In the control group given BBN alone, only 1 of 16 rats had carcinoma at Wk 28. The present findings clearly demonstrate that uracil-induced urolithiasis had a strong promoting activity on BBN bladder carcinogenesis.