Loss of DNA Mismatch Repair in Acquired Resistance to Cisplatin1

Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutations in genes involved in DNA mismatch repair and thereby to resistance to DNA-alkylating agents. Parental cells of the human ovarian adenocarcinoma cell line 2008 expressed liMI.HI when analyzed with immunoblot. One subline selected for resistance to cisplatin (2008/A) expressed no hMLHl, whereas another (2008/C 13*5.25) ex pressed parental levels. Microsatellite instability was readily demon strated in 2008/A cells but not in 2008 and in 2008/013*5.25 cells. In addition, the 2008/A cells were 2-fold resistant to methyl-nitro-nitrosoguanidine 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 of DNA mismatch repair itself contributes to cisplatin resistance, studies were carried out in isogenic pairs of cell lines proficient or defective in this function. 1IC II K), a human colon cancer cell line deficient in hMLHl function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLHl. Similarly, the human endometrial cancer cell line HEC59, which expresses no hMSH2. was 2-fold resistant to cisplatin when compared to a subline comple mented with chromosome 2 that expresses hMSH2. Therefore, the selec tion of cells for resistance to cisplatin can result in the loss of DNA mismatch repair, and loss of DNA mismatch repair in turn contributes to resistance to cisplatin.