LOSS OF DNA MISMATCH REPAIR IN ACQUIRED-RESISTANCE TO CISPLATIN

Selection of cells for resistance to cisplatin, a well-recognized muta gen, could result in mutations in genes involved in DNA mismatch repai r and thereby to resistance to DNA-alkylating agents. Parental cells o f the human ovarian adenocarcinoma cell line 2008 expressed hMLH1 when analyzed with immunoblot. One subline selected for resistance to cisp latin (2008/A) expressed no hMLH1, whereas another (2008/C135.25) exp ressed parental levels. Microsatellite instability was readily demonst rated in 2008/A cells but not in 2008 and in 2008/C135.25 cells. In a ddition, the 2008/A cells were 2-fold resistant to methyl-nitro-nitros oguanidine and had a 65-fold elevated mutation rate at the HPRT locus as compared to 2008 cells, both of which are consistent with the loss of DNA mismatch repair in these cells. To determine whether the loss o f DNA mismatch repair itself contributes to cisplatin resistance, stud ies were carried out in isogenic pairs of cell lines proficient or def ective in this function. HCT116, a human colon cancer cell line defici ent in hMLH1 function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLH1. Sim ilarly, the human endometrial cancer cell fine HEC59, which expresses no hMSH2, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 2 that expresses hMSH2. Therefore, the s election of cells for resistance to cisplatin can result in the Loss o f DNA mismatch repair, and loss of DNA mismatch repair in turn contrib utes to resistance to cisplatin.