title: P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate.
abstract: Imatinib (Glivec), STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.
authors.affiliation: Medical Clinic and Policlinic I, University Hospital of the Technical University, Dresden, Germany. illmer@mk1.med.tu-dresden.de
authors.forename: T
authors.initials: T
authors.lastname: Illmer
authors.forename: M
authors.initials: M
authors.lastname: Schaich
authors.forename: U
authors.initials: U
authors.lastname: Platzbecker
authors.forename: J
authors.initials: J
authors.lastname: Freiberg-Richter
authors.forename: U
authors.initials: U
authors.lastname: Oelschlägel
authors.forename: M
authors.initials: M
authors.lastname: von Bonin
authors.forename: S
authors.initials: S
authors.lastname: Pursche
authors.forename: T
authors.initials: T
authors.lastname: Bergemann
authors.forename: G
authors.initials: G
authors.lastname: Ehninger
authors.forename: E
authors.initials: E
authors.lastname: Schleyer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism* / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism* / Q000627:therapeutic use; D012235:Rhodamines / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; C082869:CRKL protein; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D012235:Rhodamines; D016572:Cyclosporine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl