Clinical relevance of MGMT in the treatment of cancer

Abstract

Anumber of DNA-damaging chemotherapeutic agents attack the O(6) position on guanine, forming the most potent cytotoxic DNA adducts known. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT), encoded by the gene MGMT, repairs alkylation at this site and is responsible for protecting both tumor and normal cells from these agents. Cells and tissues vary greatly in AGT expression, not only between tissues but also between individuals. AGT activity correlates inversely with sensitivity to agents that form O(6)-alkylguanine DNA adducts, such as carmustine (BCNU), temozolomide, streptozotocin, and dacarbazine. The one exception is those tumors lacking mismatch repair, which renders them resistant to methylating agents. A recent study in patients with gliomas confirmed the correlation between low-level expression of the MGMT gene and response and survival after BCNU. An inhibitor to AGT, O(6)-benzylguanine (BG), depletes AGT in human tumors without associated toxicity and is now in phase II clinical trials. Finally, mutations within the active site region of the MGMT gene render the AGT protein resistant to BG inactivation. As a result, mutant MGMT gene transfer into hematopoietic stem cells has been shown to selectively protect the marrow from the combination of an alkylating agent and BG, while at the same time sensitizing tumor cells. MGMT remains a paradigm for development of new agents that modulate known mechanisms of drug resistance in cancer cells and raise the spectra of combinatorial therapies that encompass known drug resistance mechanisms.