LOSS OF DNA MISMATCH REPAIR DUE TO KNOCKOUT OF MSH2 OR PMS2 RESULTS IN RESISTANCE TO CISPLATIN AND CARBOPLATIN

Loss of DNA mismatch repair is a common finding in hereditary nonpolyp osis colon cancer as well as in many types of sporadic human tumors. T he effect of loss of DNA mismatch repair activity on sensitivity to ci splatin and carboplatin was tested using MSH2 and PMS2 knockout cell l ines. The knockout dMsh2 embryonic stem cell line was 2.1-fold more re sistant to cisplatin and 1.7-fold more resistant to carboplatin when c ompared to the isogenic wild-type wt-2 cell line. Likewise, the PMS2(- /-) mouse fibroblasts were 1.9-fold more resistant to cisplatin and 1. 5-fold more resistant to carboplatin when compared to the isogenic PMS 2(+/+) fibroblasts. These findings demonstrate that loss of mismatch r epair due to knockout of either MSH2 or PMS2 results in low-level resi stance to cisplatin and carboplatin, drugs that form the same types of adducts in DNA. These data validate results previously obtained using non-isogenic mismatch repair-proficient and -deficient cell lines, an d indicate that simple recognition of the cisplatin adduct by the MSH2 /MSH6 heterodimer is not sufficient for full detector function, but th at PMS2 is also required for the pro-apoptotic signal to be generated from this detector.