The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia
The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia
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DOI：
10.1038/sj.bjc.6602881
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发表时间：
2005-12-12
影响因子：
8.8
通讯作者：
Kaspers, GJL
中科院分区：
文献类型：
--
作者：
Hubeek, I;Stam, RW;Kaspers, GJL
阿糖胞苷（ara-C）是治疗急性髓系白血病（AML）最有效的药物。参与 ara-C 转运/代谢的酶的异常表达可以解释耐药性。我们使用定量实时 PCR 在诊断为新发 AML 的儿童的白血病原始细胞中测定了这些因子的 mRNA 表达。与 FAB-M1/2 相比，FAB-M5 中失活酶嘧啶核苷酸酶-I (PN-I) 的表达低 1.8 倍 (P=0.007)。使用MTT测定法测定对脱氧核苷类似物的体外敏感性。人平衡核苷转运蛋白 1 (hENT1) mRNA 表达和 ara-C 敏感性显着相关 (r(p) = -0.46；P = 0.001），耐药患者中 hENT1 mRNA 水平低三倍 (P = 0.003)。 hENT1 mRNA 表达似乎也与克拉屈滨（r(p) = 0.30；P = 0.04）、地西他滨（r(p) = -0.29；P = 0.04）和吉西他滨（r(p) = 0.33；P = 0.02）的 LC50 值呈负相关。脱氧胞苷激酶 (dCK) 和胞苷脱氨酶 (CDA) mRNA 表达似乎分别与吉西他滨 (r(p) = 0.31；P = 0.03) 和地西他滨 (r(p) = 0.33；P = 0.03) 的体外敏感性相关。 dCK/PN-1 比率与吉西他滨的 LC50 值呈反比（r(p) = 0.45，P = 0.001），dCK/CDA 比率似乎与地西他滨的 LC50 值相关（r(p) = 0.29；0.04）。总之，负责跨细胞膜转运 ara-C 的 hENT1 表达下降似乎是儿童 AML 中 ara-C 耐药的主要因素。
Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (r(p) = -0.46; P = 0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P = 0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (r(p) = 0.30; P = 0.04), decitabine (r(p) = -0.29; P = 0.04) and gemcitabine (r(p) = 0.33; P = 0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (r(p) = 0.31; P = 0.03) and decitabine (r(p) = 0.33; P = 0.03), respectively. The dCK/PN-1 ratio correlated inversely with LC50 values for gemcitabine (r(p) = 0.45,P = 0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (r(p) = 0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML.