Abstract
The DNA repair and detoxifying enzymes, O(6)-methylguanine-DNA-methyltransferase (MGMT) and glutathione-S-transferase (GST), may be responsible fpr poor response to alkylating agents in glioblastoma treatment. The methylation of MGMT promoter and the expression of MGMT and GST were highly heterogeneous in surgical specimens of human glioblastoma and in established human glioblastoma cells under 2-D and 3-D culture conditions, suggesting an intrinsic property of these cells. MGMT and GST expression did not predict the sensitivity of glioblastoma cells to alkylating agents. Combination of alkylating agents with inhibitors of GST disclosed additive effects, suggesting that inhibition of GST should be considered in glioblastoma therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkylating Agents / pharmacology
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Brain Neoplasms / drug therapy
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Brain Neoplasms / enzymology*
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Carmustine / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA Methylation
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DNA Modification Methylases / genetics
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DNA Modification Methylases / metabolism*
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism*
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DNA Replication / drug effects
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Ethacrynic Acid / pharmacology
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Glioblastoma / drug therapy
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / pathology
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Glutathione S-Transferase pi / metabolism
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Glutathione Transferase / antagonists & inhibitors
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Glutathione Transferase / genetics
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Glutathione Transferase / metabolism*
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Guanine / analogs & derivatives
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Guanine / pharmacology
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Humans
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Melphalan / pharmacology
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Promoter Regions, Genetic
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Alkylating Agents
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Enzyme Inhibitors
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Tumor Suppressor Proteins
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O(6)-benzylguanine
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Guanine
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DNA Modification Methylases
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MGMT protein, human
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GSTP1 protein, human
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Glutathione S-Transferase pi
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Glutathione Transferase
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DNA Repair Enzymes
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Ethacrynic Acid
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Melphalan
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Carmustine