O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy
Related Experiment Video
Updated: Jul 30, 2026
Steady-state, Pre-steady-state, and Single-turnover Kinetic Measurement for DNA Glycosylase Activity
Published on: August 19, 2013
J R Silber1, A Blank, M S Bobola
1Department of Neurological Surgery, University of Washington, Seattle 98195-6470, USA. jrsilber@u.washington.edu
Abstract:
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) contributes to the resistance of human brain tumor cell lines and xenografts to methylating and chloroethylating agents. We assayed MGMT in 174 newly diagnosed or recurrent gliomas to (a) quantitate changes in MGMT activity associated with alkylating agent-based chemotherapy; and (b) assess the contribution of MGMT to clinical outcome. Glioma MGMT activity ranged 300-fold, averaging 3,800+/-7,200 molecules/cell. Twenty-four percent of tumors lacked detectable activity [Methyl repair-deficient (Mer-) phenotype, defined here as <151 molecules/cell or <0.25 fmol/10(6) cells]. Tumors treated with surgery alone and tumors recurring after surgery and radiotherapy did not differ significantly in frequency of the Mer- phenotype (29% versus 24%). However, the frequency of the Mer- phenotype among tumors recurring after surgery, radiation, and alkylating agent-based chemotherapy was 7-fold lower than in tumors treated with surgery alone (4.3% versus 29%; P < or = 0.02) and 6-fold lower than in tumors recurring after surgery and radiation (4.3% versus 24%; P < or = 0.05). In contrast to gliomas, there was no relationship of alkylating agent-based therapy with the frequency of the Mer- phenotype in paired histologically normal brain. These data suggest that alkylating agents, either alone or synergistically with radiotherapy, selectively kill Mer- glioma cells in situ. Importantly, Mer- and Mer+ tumors did not differ in time to tumor progression following treatment with alkylating agents, indicating that although Mer- glioma cells may be differentially killed by alkylators, factors other than Mer phenotype were the principal determinants of time to clinical progression. Nonetheless, our results support the possibility that complete ablation of glioma MGMT with substrate analogue inhibitors could improve the efficacy of alkylating agent-based chemotherapy.
Insights
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is crucial for brain tumor resistance to chemotherapy. Alkylating agents selectively target MGMT-deficient gliomas, but other factors influence treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein.
- MGMT activity influences the efficacy of DNA-alkylating chemotherapies.
- Brain tumors, particularly gliomas, exhibit variable MGMT expression.
Purpose of the Study:
- To quantify MGMT activity in gliomas.
- To assess the impact of MGMT on clinical outcomes in glioma patients.
- To investigate the selective pressure of chemotherapy on MGMT-deficient gliomas.
Main Methods:
- Assayed MGMT activity in 174 newly diagnosed or recurrent gliomas.
- Defined Methyl repair-deficient (Mer-) phenotype as <151 molecules/cell.
- Compared Mer- phenotype frequency across different treatment groups (surgery alone, surgery + radiotherapy, surgery + radiotherapy + chemotherapy).
Main Results:
- Glioma MGMT activity varied significantly (300-fold range).
- Twenty-four percent of tumors were Methyl repair-deficient (Mer-).
- Chemotherapy significantly reduced the frequency of Mer- tumors, indicating selective killing of these cells.
- MGMT phenotype did not predict time to tumor progression.
Conclusions:
- Alkylating agents, with or without radiotherapy, selectively eliminate Mer- glioma cells.
- Factors beyond MGMT status are primary determinants of clinical progression.
- Targeting MGMT with inhibitors could enhance chemotherapy efficacy for gliomas.
More Related Videos
09:24Generation of Microtumors Using 3D Human Biogel Culture System and Patient-derived Glioblastoma Cells for Kinomic Profiling and Drug Response Testing
Published on: June 9, 2016
05:45Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
