P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate.
Leukemia
; 18(3): 401-8, 2004 Mar.
Article
em En
| MEDLINE
| ID: mdl-14724652
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Pirimidinas
/
Rodaminas
/
Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Resistencia a Medicamentos Antineoplásicos
/
Proteínas Adaptadoras de Transdução de Sinal
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Alemanha