The role of DNA mismatch repair in drug resistance.

Loss of DNA mismatch repair (MMR) has been observed in a variety of human cancers. In addition to predisposing to oncogenesis, loss of MMR activity is of concern with respect to the use of chemotherapeutic agents to treat established tumors. Loss of MMR results in drug resistance directly by impairing the ability of the cell to detect DNA damage and activate apoptosis and indirectly by increasing the mutation rate throughout the genome. The MMR proteins are involved in mediating the activation of cell cycle checkpoints and apoptosis in response to DNA damage. MMR-deficient cells have been reported to be resistant to the methylating agents procarbazine and temozolomide, the alkylating agent busulfan, the platinum-containing drugs cisplatin and carboplatin, the antimetabolite 6-thioguanine, and the topoisomerase II inhibitors etoposide and doxorubicin. In the case of cisplatin, busulfan, temozolomide, and procarbazine, the degree of resistance has been shown to be sufficient to produce a large difference in clinical responsiveness in vivo 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 challenge now is to assess the clinical significance of the presence of deficient cells in tumors and to discover drugs that retain activity against MMR-deficient cells.