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

Oncogene. 2000 Jun 29;19(28):3138-45. doi: 10.1038/sj.onc.1203668.


The contributions of defective mismatch repair and mutated p53 to cisplatin resistance of human tumor cells were analysed. Mismatch repair defects were not associated with a predictable degree of resistance among several tumor cell lines. Repair defective variants of the A2780 ovarian carcinoma cell line which were isolated by selection for a methylation tolerant phenotype and did not express the hMLH1 mismatch repair protein, were highly resistant to cisplatin. Their cisplatin resistance was not a simple consequence of the mismatch repair defect. They were members of a drug-naive subpopulation of A2780 in which a silent hMLH1 gene accompanies a mutated p53. Two complementary approaches indicated that each defect contributes to cisplatin resistance independently and to a different extent. Firstly, separate introduction of a p53 defect into A2780 cells significantly increased their cisplatin 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 only slightly to cisplatin. Both approaches indicate that defective p53 status is a major determinant of cisplatin resistance and defective mismatch repair is a minor, and independent, contributor. The data have implications for the development of intrinsic cisplatin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents / pharmacology*
  • Base Pair Mismatch*
  • Carrier Proteins
  • Cisplatin / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • DNA Repair*
  • Drug Resistance, Neoplasm
  • Female
  • HT29 Cells
  • Humans
  • MutL Protein Homolog 1
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins
  • Ovarian Neoplasms
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*
  • bcl-2-Associated X Protein


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CDKN1A protein, human
  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • MutL Protein Homolog 1
  • Cisplatin