Enhancement of urinary bladder carcinogenesis in nullizygous p53-deficientmice by N-butyl-N-(4-hydroxybutyl)nitrosamine

We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, h eterozygous and nullizygous p53-deficient mice and their Littermates were t reated with the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)-nitr osamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis b ut not development of other tumors in the nullizygous p53-deficient mice. T hus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational i nactivation of the wild-type allele was not apparent in either the single t ransitional cell carcinoma observed in a wild-type mouse and a hemangiosarc oma in a heterozygote. Overall, it can be concluded that the number of norm al p53 alleles is a significant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urina ry bladder carcinogenesis may thus be to diminish the threshold for occurre nce of additional genetic alterations. (C) 1999 Elsevier Science Ireland Lt d. All rights reserved.