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

Oncogene volume 19, pages 3138–3145 (2000)Cite this article

Abstract

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-naïve 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.

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Acknowledgements

We are grateful to Dr R Brown for A2780 and A2780CP70 cells and to Drs M Liskay and A Buermeyer for the hMLH1 cDNA clone. We also thank Mr Peter Macpherson for assistance in mismatch repair assays and the ICRF Clare Hall Cell production team for providing cells. M Masson was a recipient of a Marie Curie training fellowship from the European Union.

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Authors and Affiliations

  1. Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts, EN6 3LD, UK

    P Branch, M Masson & P Karran

  2. Istituto Superiore di Sanitá, Viale Regina Elena 299, Rome, 00161, Italy

    G Aquilina & M Bignami

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  1. P Branch
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Branch, P., Masson, M., Aquilina, G. et al. Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells. Oncogene 19, 3138–3145 (2000). https://doi.org/10.1038/sj.onc.1203668

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