Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity.

Abstract

Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

• Authors: Monika E Hegi, Lili Liu, James G Herman, Roger Stupp, Wolfgang Wick, Michael Weller, Minesh P Mehta, Mark R Gilbert
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 26 Issue 25 Pg. 4189-99 (Sep 01 2008) ISSN: 1527-7755 [Electronic] United States
• PMID: 18757334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents, Alkylating
• O(6)-Methylguanine-DNA Methyltransferase

Topics

• Antineoplastic Agents, Alkylating (pharmacology)
• Brain Neoplasms (drug therapy, genetics)
• CpG Islands
• DNA Methylation
• Gene Silencing
• Glioblastoma (drug therapy, genetics)
• Glioma (drug therapy, genetics)
• Humans
• Maximum Tolerated Dose
• Medical Oncology (methods)
• Models, Chemical
• O(6)-Methylguanine-DNA Methyltransferase (genetics)
• Promoter Regions, Genetic
• RNA Interference
• Treatment Outcome