Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine-methyltransferase.
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.
Juillerat-Jeanneret
Lucienne
L
University Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. lucienne.juillerat@chuv.ch
Bernasconi
Catherine Chapuis
CC
Bricod
Charlotte
C
Gros
Solange
S
Trepey
Sylviane
S
Benhattar
Jean
J
Janzer
Robert C
RC
D000477:Alkylating Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008558:Melphalan / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D045643:DNA Repair Enzymes; D004976:Ethacrynic Acid; D008558:Melphalan; D002330:Carmustine