Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

The contributions of defective mismatch repair and mutated p53 to cisplatin resistance of human tumor cells were analysed. Mismatch repair defects wer e not associated with a predictable degree of resistance among several tumo r cell Lines. Repair defective variants of the A2780 ovarian carcinoma cell Line which were isolated 62 selection for a methylation tolerant phenotype and did not express the hMLH1 mismatch repair protein, were highly resista nt to cisplatin, Their cisplatin resistance was not a simple consequence of the mismatch repair defect. They were members of a drug-naive subpopulatio n of A2780 in which a silent hMLH1 gene accompanies a mutated p53. Two comp lementary approaches indicated that each defect contributes to cisplatin re sistance independently and to a different extent, Firstly separate introduc tion of a p53 defect into A2780 cells significantly increased their cisplat in resistance; defective hMLH1 provided less extensive protection. Secondly , azadeoxycytidine reactivation of the silent hMLH1 gene or expression of a transfected hMLH1 cDNA sensitized the doubly hMLH1/p53 deficient cells onl y slightly to cisplatin, Both approaches indicate that defective p53 status is a major determinant of cisplatin resistance and defective mismatch repa ir is a minor, and independent, contributor. The data have implications for the development of intrinsic cisplatin resistance.