title: Evaluation of the clinical relevance of the expression and function of P-glycoprotein, multidrug resistance protein and lung resistance protein in patients with primary acute myelogenous leukemia.
abstract: The multidrug resistance (MDR) transporter-proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance protein (LRP) have been associated with treatment failure. The aim of this study was to investigate prospectively the clinical significance of expression and function of the MDR proteins, considering other prognostic factors, such as age, immunophenotype, and cytogenetics. Mononuclear cells of peripheral blood or bone marrow from 61 patients with de novo acute myelogenous leukemia (AML) were analyzed. The monoclonal antibodies JSB1, MRPm6 and LRP56 were used for expression studies. Accumulation and retention studies were performed using the substrates Daunorubicin, Calcein-AM, Rhodamine-123 and DiOC(2) in the presence or absence of the modifiers Verapamil, Genistein, Probenecid, BIBW22S and PSC833. Induction treatment consisted of a 3+7 combination of Ida/Ara-C for patients < or = 60 years of age and a 3+5 Ida/VP-16 combination per OS for patients >60. MDR function was expressed as the ratio of mean fluorescence intensity substrate in the presence of modifier over the substrate alone (resistance index, RI). Patients with advanced age, low CD15 expression and high RI for accumulation of DiOC(2) in the presence of BIBW22S had significantly lower complete remission (CR) rates. No factor was prognostic for event-free survival analysis, which was limited to remitters only. Overall survival was shorter in patients with advanced age, poor prognosis cytogenetics, high CD7 expression, and high RI for Daunorubicin efflux modulated by Verapamil. These results suggest that MDR transporter-proteins have a limited role in the treatment failure of patients treated with Idarubicin-based regimens.
authors.affiliation: Department of Internal Medicine, The University of Athens, Athens 11527, Greece. atsimber@mail.mdanderson.org
authors.forename: Apostolia Maria
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: George
authors.initials: G
authors.lastname: Paterakis
authors.forename: George
authors.initials: G
authors.lastname: Androutsos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Anagnostopoulos
authors.forename: Athanasios
authors.initials: A
authors.lastname: Galanopoulos
authors.forename: Themistoklis
authors.initials: T
authors.lastname: Kalmantis
authors.forename: John
authors.initials: J
authors.lastname: Meletis
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Rombos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Sagriotis
authors.forename: Argyrios
authors.initials: A
authors.lastname: Symeonidis
authors.forename: Maria
authors.initials: M
authors.lastname: Tiniakou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Zoumbos
authors.forename: Xenophon
authors.initials: X
authors.lastname: Yataganas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002232:Carbocyanines / Q000378:metabolism; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000378:metabolism; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011339:Probenecid / Q000494:pharmacology; D011379:Prognosis; D011446:Prospective Studies; D020112:Rhodamine 123 / Q000378:metabolism; D016019:Survival Analysis; D014407:Tumor Cells, Cultured / Q000378:metabolism; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D002232:Carbocyanines; D003561:Cytarabine; D003630:Daunorubicin; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D005456:Fluorescent Dyes; D019833:Genistein; D015255:Idarubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011339:Probenecid; D020112:Rhodamine 123; D020394:Vault Ribonucleoprotein Particles; D014700:Verapamil; D000099187:Major Vault Protein; C085925:calcein AM; C081554:3,3'-diethyloxacarbocyanine; C421109:multidrug resistance-associated protein 1