Role of p53 in the responses of human urothelial cells to genotoxic damage

Loss of p53 function is a feature of many types of malignancy, including tr ansitional-cell carcinoma (TCC), where it is associated with high-grade les ions and the development of muscle-invasive disease. Genotoxic: agents used as part of the treatment strategy may contribute to tumour progression by inducing further non-lethal DNA damage in surviving cells. To determine the role of p53 in cellular responses to genotoxic agents, we used cultured no rmal human urothelial (NHU) cells and NHU cells with disabled p53 function. Mitomycin C and gamma -radiation caused normal cells to undergo an extende d period of cell-cycle arrest, followed by complete recovery of proliferati ve potential. In contrast, cells with disabled p53 function, whether karyot ypically normal (HU-EB cells) or post-crisis with karyotypic abnormalities (HU-E6P cells), underwent extensive apoptosis. Overall survival was dose-de pendent, and surviving HU-E6 cells from low-dose treatments showed clonal k aryotypic abnormalities. These findings demonstrate that p53 status is a cr ucial factor in determining the ability of urothelial cells to survive DNA damage and suggest caution in the use of genotoxic treatments for low-grade tumours as our data imply that malignancies that have not yet lost p53 fun ction will show the same "repair-and-recovery" response as normal cells. (C ) 2001 Wiley-Liss, Inc.