Journal of Clinical Oncology, Vol 20, Issue 9
(May), 2002: 2388-2399
© 2002 American Society for Clinical Oncology
Clinical Relevance of MGMT in the Treatment of Cancer
By Stanton L. Gerson
From the Division of Hematology/Oncology and Comprehensive Cancer Center, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, and The University Hospitals Research Institute, Cleveland, OH.
Address reprint requests to Stanton L. Gerson, MD, Division of Hematology/Oncology, Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, BRB 3 West, Cleveland, OH 44106-4937; email: slg5{at}po.cwru.edu
ABSTRACT: A number of DNA-damaging chemotherapeutic agents attack the O6 position on guanine, forming the most potent cytotoxic DNA adducts known. The DNA repair enzyme O6-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 O6-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, O6-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.
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