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.
Subject(s)
Brain Neoplasms/enzymology , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , Glioblastoma/enzymology , Glutathione Transferase/metabolism , Tumor Suppressor Proteins/metabolism , Alkylating Agents/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Carmustine/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Methylation , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , DNA Replication/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Ethacrynic Acid/pharmacology , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Glutathione S-Transferase pi/metabolism , Glutathione Transferase/antagonists & inhibitors , Glutathione Transferase/genetics , Guanine/analogs & derivatives , Guanine/pharmacology , Humans , Melphalan/pharmacology , Promoter Regions, Genetic , Tumor Suppressor Proteins/geneticsABSTRACT
We investigated whether the determination of clonality by polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain (IgH) gene rearrangements could be helpful in the evaluation of B-cell lymphoma (BCL) involvement of bone marrow (BM) biopsy specimens. We evaluated 83 paraffin-embedded BM biopsy specimens from 26 patients with BCL. When BM biopsy specimens considered positive, "suspicious," or negative by morphologic and immunohistochemical examination were evaluated by PCR, a monoclonal B-cell population was detected in 81% (39/48), 64% (9/14), and 11% (2/18), respectively. In most cases, a reproducible monoclonal IgH gene rearrangement was observed from BM and extramedullary sites. Nevertheless, in 4 cases, a different and independent monoclonal IgH rearrangement was observed during the disease course. PCR is efficient and complementary to morphologic and immunohistochemical examination for the evaluation of BCL involvement of BM biopsy specimens, especially when a reproducible rearrangement is found in 2 different samples.