RESISTANCE TO CYTOTOXIC DRUGS IN DNA MISMATCH REPAIR-DEFICIENT CELLS

Loss of DNA mismatch repair is a common finding in many types of spora dic human cancers as well as in tumors arising in patients with heredi tary nonpolyposis colon cancer, The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemothera peutic agents was tested using one pair of cell lines proficient or de ficient in mismatch repair due to loss of hMSH2 function and another d ue to loss of hMLH1 function, 6-Thioguanine and N-methyl-N'-nitro-N-ni trosoguanidine, to which these cells are known to be resistant, were i ncluded in the panel as controls, The results were concordant in both pairs of cells, Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, bu t there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel, The results are consistent with the concep t that the DNA mismatch repair proteins function as a detector for add ucts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide, The y also suggest that these proteins play a role in detecting the DNA da mage produced by the binding of etoposide to topoisomerase II and prop agating signals that contribute to activation of apoptosis.