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

Details

Serval ID
serval:BIB_81D488177048
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity.
Journal
Journal of Clinical Oncology
Author(s)
Hegi M.E., Liu L., Herman J.G., Stupp R., Wick W., Weller M., Mehta M.P., Gilbert M.R.
ISSN
1527-7755[electronic]
Publication state
Published
Issued date
2008
Volume
26
Number
25
Pages
4189-4199
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Review
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.
Keywords
Antineoplastic Agents, Alkylating/pharmacology, Brain Neoplasms/drug therapy, Brain Neoplasms/genetics, CpG Islands, DNA Methylation, Gene Silencing, Glioblastoma/drug therapy, Glioblastoma/genetics, Glioma/drug therapy, Glioma/genetics, Humans, Maximum Tolerated Dose, Medical Oncology/methods, Models, Chemical, O(6)-Methylguanine-DNA Methyltransferase/genetics, Promoter Regions, Genetic, RNA Interference, Treatment Outcome
Pubmed
Web of science
Create date
29/01/2009 22:13
Last modification date
20/08/2019 14:42
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