WILD-TYPE P53 PROTEIN POTENTIATES CYTOTOXICITY OF THERAPEUTIC AGENTS IN HUMAN COLON-CANCER CELLS

Wild-type p53 is induced by DNA damage. In different cell types, this induction is suggested either to facilitate DNA repair by inducing a c ell cycle pause or to potentiate cell death via apoptosis, Wild-type p 53 in different cell types has similarly been associated with either e nhancement of or increased resistance to the cytotoxicity of many canc er therapeutic agents. We have constructed a colorectal cancer cell li ne bearing, in addition to endogenous mutant p53 alleles, an exogenous wild-type p53 allele that is under the regulatable control of the lac repressor, Induction of wild-type p53 by isopropyl-beta-thiogalactopy ranoside in these cells induces a reversible growth arrest but does no t induce cell death, However, we find that the induction of wild-type p53 powerfully potentiates the cytotoxicity of both irradiation and 5- fluorouracil, two agents that are used clinically in the treatment of colorectal cancer, We also find that induction of wild-type p53 potent iates the cytotoxicity of topotecan, a member of the camptothecin fami ly of drugs that also has clinical activity against colon cancer, Thes e findings suggest that the common loss of wild-type p53 in many color ectal cancers may play a role in the clinical resistance of these tumo rs to anticancer agents, Although some cancer cells may not be directl y killed by p53 gene therapy, our findings suggest that genetic altera tion of some cancers to induce wild-type p53 may increase their sensit ivity to cytotoxic gene therapy.