Glutathione system, topoisomerase II level and multidrug resistance phenotype in acute myelogenous leukemia before treatment and at relapse.
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.
Massaad-Massade
L
L
Département de Pharmacotoxicologie et de Pharmacogénétique, CNRS URA 147, Institut Gustave-Roussy, Villejuif, France.
Ribrag
V
V
Marie
J P
JP
Faussat
A M
AM
Bayle
C
C
Dreyfus
F
F
Gouyette
A
A
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
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