Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlägel U, von Bonin M, Pursche S, Bergemann T, Ehninger G, Schleyer E
Medical Clinic and Policlinic I, University Hospital of the Technical University, Dresden, Germany.
Leukemia. 2004 Mar;18(3):401-8. doi: 10.1038/sj.leu.2403257.
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.
伊马替尼（格列卫，STI571）是一种作用于细胞内的药物，对BCR-ABL阳性的慢性粒细胞白血病（CML）或急性淋巴细胞白血病（ALL）具有高活性。然而，许多患者，尤其是晚期疾病患者，会产生耐药性。在此，我们通过一种基于新型高效液相色谱的方法表明，在P-糖蛋白（Pgp）阳性的白血病细胞中，伊马替尼的细胞内水平会降低。在Pgp表达逐渐增加的K562细胞模型中，观察到细胞内伊马替尼水平呈Pgp依赖性下降。伊马替尼水平降低与Bcr-Abl靶点Crkl的磷酸化模式保留以及伊马替尼对细胞增殖和凋亡的作用丧失有关。环孢素A（CSA）对Pgp的调节可迅速恢复这些细胞中伊马替尼的细胞毒性。最后，我们提供了首个数据，显示Pgp调节在伊马替尼治疗BCR-ABL阳性ALL患者中的生物学效应。因此，MDR1过表达必须被视为伊马替尼治疗耐药性产生多样性的重要临床机制。
