Lack of involvement of p53 gene mutations in N-methyl-N-nitrosourea-induced bladder tumor progression in N-butyl-N-(4-hydroxybutyl)nitrosamine-treated rats and no suppression by indomethacin

The relevance of p53 mutations to rat bladder cancer progression induced by a single injection of N-methyl-N-nitrosourea (MNU) and the chemopreventive effects of indomethacin (IM) were investigated in male F344 rats, initially given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at a dose of 500 ppm in the drinking water for 10 weeks. The animals were subsequently treated with a single intraperitoneal injection of MNU at a dose of 50 mg/kg b.w. at week 20. A subgroup was then given IM dissolved in the drinking water at a concentration of 20 ppm for 20 weeks. The experiment was terminated at week 40 when transitional cell carcinomas (TCC) were observed in all animals given BBN, regardless of the administration of MNU and/or IM (incidences ranged from 80 to 100%). The extent of invasion was significantly greater with the additional MNU treatment but no inhibitory effects of IM were noted. A low frequency of p53 mutations was detected without relation to the extent of tumor invasion. Thus, only two mutations were found, one in a Ta and the other in a T1 carcinoma. The present study thus demonstrated that p53 mutations are not involved in MNU-induced progression in rat urinary bladder cancers, suggesting that they are not critical for malignancy.