The role of DNA mismatch repair in platinum drug resistance.
Loss of DNA mismatch repair occurs in many types of tumors. The effect of the loss of DNA mismatch repair activity on sensitivity to cisplatin and a panel of analogues was tested using two pairs of cell lines proficient or deficient in this function. HCT116+ch2, a human colon cancer cell line deficient in hMLH1, was 2.1-fold resistant to cisplatin and 1.3-fold resistant to carboplatin when compared to a subline complemented with chromosome 3 expressing a wild-type copy of hMLH1. Likewise, the human endometrial cancer cell line HEC59, which is deficient in hMSH2, was 1.8-fold resistant to cisplatin and 1.5-fold resistant to carboplatin when compared to a subline complemented with chromosome 2 with a wild-type hMSH2. In contrast to cisplatin and carboplatin, which form the same types of adducts in DNA, there was no difference in sensitivity between the DNA mismatch repair-proficient and -deficient cell lines for oxaliplatin, tetraplatin, transplatin, JM335, or JM216. The formation of protein-DNA complexes that contained hMSH2 and hMLH1 was documented by mobility shift assay when nuclear extracts were incubated with DNA platinated with cisplatin but not with oxaliplatin. These results demonstrate a correlation between failure of the DNA mismatch repair proteins to recognize the platinum adduct and low-level resistance, suggesting a role for the DNA mismatch repair system in generating signals that contribute to the generation of apoptotic activity. They also identify the use of drugs whose adducts are not recognized as a strategy for circumventing resistance due to loss of DNA mismatch repair.
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla 92093-0058, USA.
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Fink
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Zheng
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Christen
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Howell
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004351:Drug Resistance; D005260:Female; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D016190:Carboplatin; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin