In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia
In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia
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DOI：
10.1046/j.1365-2141.2002.03538.x
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发表时间：
2002-06-01
影响因子：
6.5
通讯作者：
Dumontet, C
中科院分区：
文献类型：
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作者：
Galmarini, CM;Thomas, X;Dumontet, C
降低三磷酸化阿糖胞苷（ara-CTP）（阿糖胞苷（ara-C）的活性形式）细胞内浓度的因素可能会诱导急性髓性白血病（AML）患者的化疗耐药。这些因素包括hENT 1转运蛋白减少的ara-C内流，脱氧胞苷激酶（dCK）减少的磷酸化，以及高Km细胞质5 '-核苷酸酶（5 NT）和/或胞苷脱氨酶（CDD）增加的降解。在阿糖胞苷耐药细胞系中也检测到DNA聚合酶α（DNA POL）水平升高，拓扑异构酶I（TOPO I）和拓扑异构酶II（TOPO II）水平降低。为了确定这些因素是否与临床阿糖胞苷耐药有关，我们分析了这些参数在诊断时的表达，使用逆转录聚合酶链反应，在123例阿糖胞苷治疗的AML患者的母细胞中。hENT 1、dCK、CDD、5 NT、TOPO I、TOPO II、DNA POL和MDR 1的阳性率分别为83%、22%、7%、37%、59%、37%、39%和16%。在单因素分析中，诊断时表达5 NT或DNA POL的患者无病生存期（DFS）显著缩短。在多因素分析中，DNA POL阳性和hENT 1缺陷与较短的DFS相关。在单变量分析中，5 NT阳性原始细胞的患者的总生存期（OS）显着较短。在多变量分析中，较短的OS与DNA POL阳性相关。这些结果表明，DNA POL，5 NT和hENT 1的表达在诊断AML患者对阿糖胞苷耐药的机制可能。
Factors that reduce the intracellular concentration of triphosphorylated cytarabine (ara-CTP), the active form of cytarabine (ara-C), may induce chemoresistance in acute myeloid leukaemia (AML) patients. These factors include reduced influx of ara-C by the hENT1 transporter, reduced phosphorylation by deoxycytidine kinase (dCK), and increased degradation by high Km cytoplasmic 5'-nucleotidase (5NT) and/or cytidine deaminase (CDD). Increased levels of DNA polymerase alpha (DNA POL) and reduced levels of topoisomerase I (TOPO I) and topoisomerase II (TOPO II) have also been detected in ara-C-resistant cell lines. To determine whether these factors are implicated in clinical ara-C resistance, we analysed the expression of these parameters at diagnosis, using reverse transcription polymerase chain reaction, in the blast cells of 123 AML patients treated with ara-C. At diagnosis, hENT1, dCK, CDD, 5NT, TOPO I, TOPO II, DNA POL and MDR1 were expressed in 83%, 22%, 7%, 37%, 59%, 37%, 39% and 16% of patients respectively. In univariate analysis, patients with expression of 5NT or DNA POL at diagnosis had significantly shorter disease-free survival (DFS). In multivariate analysis, DNA POL positivity and hENT1 deficiency were related to a shorter DFS. In univariate analysis, patients with 5NT-positive blasts had significantly shorter overall survival (OS). In multivariate analysis, shorter OS was related to DNA POL positivity. These results suggest that expression of DNA POL, 5NT and hENT1 at diagnosis may be resistance mechanisms to ara-C in AML patients.