CISPLATIN, CAMPTOTHECIN, AND TAXOL SENSITIVITIES OF CELLS WITH P53-ASSOCIATED MULTIDRUG-RESISTANCE

With the use of clonogenic survival assays, we show that wildtype p53- expressing A2780 human ovarian cell lines transfected with a dominant negative mutant p53 gene (codon 143, valine to alanine) acquired cross -resistance to ionizing radiation, cisplatin, doxorubicin, and 1-beta- D-arabinofuranosylcytosine. However, these mutant p53-transfected cell lines retained sensitivity to taxol and camptothecin. We also show th at immature thymocytes from mice with the p53 gene genetically inactiv ated showed reduced ability to undergo apoptosis after treatment with ionizing radiation and cisplatin compared with wild-type mice. However , taxol-induced apoptosis in thymocytes does not seem to be dependent on p53 status. Camptothecin also induced apoptosis in a p53-independen t manner in thymocytes at low doses but in a p53-dependent manner at h igh doses. These data suggest that taxoids and camptothecin analogs co uld have activity in tumors that have aberrant p53 function and provid e a rationale for the clinical observations of responsiveness of refra ctory ovarian cancer to these drugs.