ACUTE OVEREXPRESSION OF WT P53 FACILITATES ANTICANCER DRUG-INDUCED DEATH OF CANCER AND NORMAL-CELLS

The relationship between chemosensitivity and p53 is currently conside red from two mutually exclusive points of view: (1) wt p53 increases c hemosensitivity due to apoptosis and (2) wt p53 decreases chemosensiti vity due to growth arrest and DNA repair. We used p53-expressing adeno virus (Ad-p53) to directly evaluate effect of p53 on sensitivity to an ticancer drugs. When p53 was expressed at sublethal levels, it sensiti zed cells to the DNA-damaging drugs Adriamycin, mitomycin C, actinomyc in D, etoposide (VP16), cisplatin and CPT11. This sensitization was ob served in cancer cell lines (N = 10) regardless of endogenous p53 stat us and also in normal human lung and skin fibroblasts. The degree of s ensitization appeared to be greater in cancer cells with mutant p53. N ormal fibroblasts required significantly higher doses of Ad-p53 to aff ect a drug's sensitivity partly because of their lower infectivity by adenovirus. Wt p53 not only decreased IC50 but also accelerated cell d eath induced by DNA-damaging drugs. In contrast, sensitization to micr otubule-active drugs by p53 was shown only in a few cell lines. We con clude that exogenous wt p53 accelerates cell death induced by DNA dama ging agents in both normal and cancer cells and offers no protection f rom anticancer drugs. (C) 1998 Wiley-Liss, Inc.