THE ROLE OF DNA MISMATCH REPAIR IN DRUG-RESISTANCE

Loss of DNA mismatch repair (MMR) has been observed in a variety of hu man cancers, In addition to predisposing to oncogenesis, loss of MMR a ctivity is of concern with respect to the use of chemotherapeutic agen ts to treat established tumors, Loss of MMR results in drug resistance directly by impairing the ability of the cell to detect DNA damage an d activate apoptosis and indirectly by increasing the mutation rate th roughout the genome, The MMR proteins are involved in mediating the ac tivation of cell cycle checkpoints and apoptosis in response to DNA da mage. MMR-deficient cells have been reported to be resistant to the me thylating agents procarbazine and temozolomide, the alkylating agent b usulfan, the platinum-containing drugs cisplatin and carboplatin, the antimetabolite 6-thioguanine, and the topoisomerase II inhibitors etop oside and doxorubicin. In the case of cisplatin, busulfan, temozolomid e, and procarbazine, the degree of resistance has been shown to be suf ficient to produce a large difference in clinical responsiveness in vi vo in tumor model systems, The available preclinical data suggest that tumors that contain a significant fraction of cells deficient in MMR will demonstrate reduced responsiveness to specific drugs, The challen ge now is to assess the clinical significance of the presence of defic ient cells in tumors and to discover drugs that retain activity agains t MMR-deficient cells.