Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5′-nucleotidase II expression ratio in primary acute myeloid leukemia cells
Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5′-nucleotidase II expression ratio in primary acute myeloid leukemia cells
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DOI：
10.1016/j.bcp.2009.03.011
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发表时间：
2009-06-15
影响因子：
5.8
通讯作者：
Ueda, Takanori
中科院分区：
文献类型：
--
作者：
Yamauchi, Takahiro;Negoro, Eiju;Ueda, Takanori
阿糖胞苷（ara-C）是治疗急性髓系白血病（AML）的关键药物。 ara-C被人平衡核苷转运蛋白1（hENT1）转运到白血病细胞后，被磷酸化为活性代谢物ara-C三磷酸（ara-CTP），然后掺入DNA中，从而抑制DNA合成。脱氧胞苷激酶 (dCK) 和胞质 5'-核苷酸酶 II (cN-II) 与 ara-CTP 的产生相关。由于 ara-C 的细胞毒性取决于 ara-CTP 的产生，因此与 ara-CTP 形成最相关的参数可以预测 ara-C 的敏感性和 ara-C 治疗的临床结果。本研究的重点是寻找产生 ara-CTP 的能力和 ara-C 代谢因子之间的相关性。在来自 33 名白血病患者（其中 26 名患有 AML）的 34 个原始样本中评估了体外 ara-CTP 的产生、hENT1、dCK 和 cN-II 的 mRNA 水平以及 ara-C 敏感性。产生 ara-CTP 的能力以及 hENT1、dCK 和 cN-II 的 mRNA 水平存在很大程度的异质性。尽管每种转录物水平与 ara-CTP 产生之间缺乏任何关联，但 dCK/cN-II 转录物水平的比率与 AML 样本中 ara-CTP 的量显着相关。类似地评估了 HL-60 培养的白血病细胞系及其三种 ara-C 耐药变体（HL-60/R1、HL-60/R2、HL-60/R3），它们的耐药性分别是 HL-60 的 8、10 和 500 倍。 dCK/cN-II 比率再次与 ara-CTP 产量和 ara-C 敏感性成正比。因此，dCK/cN-II 比率可以预测 ara-CTP 产生的能力，并最终预测 AML 中的 araC 敏感性。 (c) 2009 Elsevier Inc. 保留所有权利。
Cytarabine (ara-C) is the key agent for treating acute myeloid leukemia (AML). After being transported into leukemic cells by human equilibrative nucleoside transporter 1 (hENT1), ara-C is phosphorylated to ara-C triphosphate (ara-CTP), an active metabolite, and then incorporated into DNA, thereby inhibiting DNA synthesis. Deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase II (cN-II) are associated with the production of ara-CTP. Because ara-C's cytotoxicity depends on ara-CTP production, parameters that are most related to ara-CTP formation would predict ara-C sensitivity and the clinical outcome of ara-C therapy. The present study focused on finding any correlation between the capacity to produce ara-CTP and ara-C-metabolizing factors. In vitro ara-CTP production, mRNA levels of hENT1, dCK, and cN-II, and ara-C sensitivity were evaluated in 34 blast samples from 33 leukemic patients including 26 with AML. A large degree of heterogeneity was seen in the capacity to produce ara-CTP and in mRNA levels of hENT1, dCK, and cN-II. Despite the lack of any association between each of the transcript levels and ara-CTP production, the ratio of dCK/cN-II transcript levels correlated significantly with the amount of ara-CTP among AML samples. The HL-60 cultured leukemia cell line and its three ara-C-resistant variants (HL-60/R1, HL-60/R2, HL-60/R3), which were 8-, 10, and 500-fold more resistant than HL-60, respectively, were evaluated similarly. The dCK/cN-II ratio was again proportional to ara-CTP production and to ara-C sensitivity. The dCK/cN-II ratio may thus predict the capacity for ara-CTP production and ultimately, araC sensitivity in AML. (c) 2009 Elsevier Inc. All rights reserved.