Leisewitz Andrea V, Zimmerman Eric I, Jones Shannon Z, Yang Jing, Graves Lee M
Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):779-86. doi: 10.1080/15257770802145892.
Philadelphia chromosome-positive chronic myelogenus leukemia (CML) is widely treated with imatinib mesylate (imatinib), a potent inhibitor of the Bcr-Abl tyrosine kinase. However, resistance to this compound remains a concern. Current treatment approaches include combinations of imatinib with nucleoside analogs such as gemcitabine, which requires equilibrative nucleoside transporters (ENTs) for uptake, to overcome this resistance. Here we report that imatinib treatment decreased ENT1-dependent activity and mRNA expression. Although, imatinib-resistant cells showed decreased levels of both ENT1 and ENT2 activity and expression, these cells remained sensitive to gemcitabine, suggesting that nucleoside analogs can be used as adjunctive therapy.
费城染色体阳性慢性髓性白血病（CML）广泛采用甲磺酸伊马替尼（伊马替尼）治疗，它是一种有效的Bcr-Abl酪氨酸激酶抑制剂。然而，对这种化合物的耐药性仍然是一个问题。目前的治疗方法包括将伊马替尼与核苷类似物（如吉西他滨）联合使用，吉西他滨需要平衡核苷转运体（ENTs）来摄取，以克服这种耐药性。在此我们报告，伊马替尼治疗降低了ENT1依赖性活性和mRNA表达。虽然伊马替尼耐药细胞显示ENT1和ENT2的活性及表达水平均降低，但这些细胞对吉西他滨仍敏感，这表明核苷类似物可作为辅助治疗药物。
