Role of mismatch repair and MGMT in response to anticancer therapies.
Tumor resistance to cytotoxic chemotherapy drugs and their toxicity to normal cells are major clinical obstacles to anticancer therapy effectiveness. Alterations in various DNA repair pathways play a key role in the development of both mechanisms of drug resistance and toxicity. Since deregulation of the DNA damage response and alterations in DNA repair pathways are relatively common in human cancer, the knowledge of these alterations in cancer cells would be an important predictive factor for the clinical response to chemotherapy and a useful guide in designing an appropriate therapeutic strategy. This review is focused on the mismatch repair (MMR) pathway and the O(6)-methylguanine-DNA-methyltransferase (MGMT) repair protein. In particular, we examine how inactivation of these DNA repair mechanisms might affect the response of tumor cells to chemotherapy, with a special emphasis on agents inducing methylation and oxidative DNA damage and interstrand DNA cross-links (ICLs). In addition, we provide novel experimental evidence indicating that MMR is required for efficient repair of ICLs via stabilization of RAD51 containing repair intermediates. Finally, we discuss possible emerging therapeutical strategies for treating MMR-defective tumors.
Casorelli
Ida
I
Section of Experimental Carcinogenesis, Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.
Russo
Maria Teresa
MT
Bignami
Margherita
M
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004249:DNA Damage / Q000187:drug effects*; D053843:DNA Mismatch Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D019853:O(6)-Methylguanine-DNA Methyltransferase