FUNCTIONAL p53 MUTATION AS A MOLECULAR DETERMINANT OF PACLITAXEL AND GEMCITABINE SUSCEPTIBILITY IN HUMAN BLADDER CANCER

Abstract

Paclitaxel and gemcitabine are promising new agents for treatment of human bladder cancer. We determine how the presence or absence of p53 function impacts the cytotoxic effects of these chemotherapeutic agents in human bladder cancer. The J82 human bladder cancer (TCC) cell line was transfected with a temperature sensitive p53 (tsp53) mutant that functions as mutated p53 at 37C but functions as wild-type (normal) p53 at 32C. Susceptibility of these inducible p53 TCC cells to paclitaxel and gemcitabine induced cytotoxicity was evaluated and kill significance determined between sub-lethal and lethal doses. Significant paclitaxel dose dependent cytotoxicity was observed in J82 TCC cells lacking normal p53 and tsp53 transfected cells at 37C, which was the mutant p53 temperature in transfectants between maximal and minimal kill concentrations for either (p <0.001). Likewise, significant cytotoxicity was observed in parental J82 TCC at 32C (p <0.001), while restoration of p53 function in tsp53 transfected cells on shift to 32C abrogated significant dose dependent cytotoxicity. Gemcitabine caused significant cell death in the cell lines incubated at either temperature and, thus, was equally effective regardless of cellular p53 function (p <0.001, respectively). Paclitaxel requires functionally mutated p53 to induce cell death in human bladder cells, indicating that it may be more effective against TCC with p53 mutations than against TCC, which lacks p53 abnormalities, while gemcitabine is effective regardless of p53 function. These findings provide a rationale for selecting chemotherapy based on the p53 status of individual bladder cancers.