title: Glutathione system, topoisomerase II level and multidrug resistance phenotype in acute myelogenous leukemia before treatment and at relapse.
abstract: In order to better understand acquired resistance to antitumor agents in acute myelogenous leukemia (AML), we investigated various drug resistance mechanisms; namely, topoisomerase II (topo II), glutathione system and P-glycoprotein (P-gp). Blast cells of 31 patients with AML, 21 before treatment (BT) and 10 at relapse (AR) were studied. Topo II was evaluated by Western blot analysis. Glutathione-S-transferase activity (GST) and glutathione content (GSH) were investigated by spectrophotometric assays. GST isoenzymes (-alpha, -mu and -pi) were tested by Western blot and by immunocytochemical staining. P-gp was evaluated by an immunocytochemical method using MRK 16 antibody. Our results showed that GST, GSH and GST-pi were similar in patients BT and AR GST-mu was detected in 13/21 AML BT and in 5/10 AML AR. GST-alpha expression was higher (p < 0.05) in AML AR (60 +/- 105 AU/mg) compared to AML BT (10 +/- 10 AU/mg). A relationship was found between GST-pi quantitation evaluated by Western blot and immunocytochemical staining, whereas no correlation was observed for the other isoenzymes. Topo II was detected in only 4 AML BT and 3 AML AR. Eleven out of 21 AML BT and 3/10 AML AR expressed P-gp with immunohistochemical study. These results indicate that only the "glutathione system", especially the GST-alpha could be involved in drug resistance in AML.
authors.affiliation: Département de Pharmacotoxicologie et de Pharmacogénétique, CNRS URA 147, Institut Gustave-Roussy, Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Massaad-Massade
authors.forename: V
authors.initials: V
authors.lastname: Ribrag
authors.forename: J P
authors.initials: JP
authors.lastname: Marie
authors.forename: A M
authors.initials: AM
authors.lastname: Faussat
authors.forename: C
authors.initials: C
authors.lastname: Bayle
authors.forename: F
authors.initials: F
authors.lastname: Dreyfus
authors.forename: A
authors.initials: A
authors.lastname: Gouyette
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000096:biosynthesis; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008130:Lomustine / Q000008:administration & dosage; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D012008:Recurrence; D012074:Remission Induction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D007527:Isoenzymes; D003561:Cytarabine; D008130:Lomustine; D005982:Glutathione Transferase; D004250:DNA Topoisomerases, Type II; D005978:Glutathione