Genetic factors influencing cytarabine therapy.
Genetic factors influencing cytarabine therapy.
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DOI：
10.2217/pgs.09.118
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发表时间：
2009-10
期刊：
影响因子：
2.1
通讯作者：
Lamba JK
中科院分区：
文献类型：
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作者：
Lamba JK
核苷类似物阿糖胞苷(Ara-C)是急性髓系白血病化疗的主要药物。大量研究表明，Ara-C活性代谢物Ara-CTP的细胞内浓度在不同患者之间差异很大，进而与急性髓系白血病治疗的临床反应的差异有关。因此，Ara-C代谢途径中关键基因的遗传变异--特别是脱氧胞苷激酶(一种限速激活酶)、5‘核苷酸酶、胞苷脱氨酶和脱氧胞苷脱氨酶(这三种酶都是失活酶)、人类平衡核苷转运体(Ara-C摄取转运体)和核糖核苷酸还原酶(RRM1和RRM2-调节细胞内脱氧胞苷三磷酸池的酶)--构成了观察到的细胞内Ara-CTP浓度和对Ara-C反应的患者间差异的分子基础。了解参与Ara-C代谢激活的关键候选基因中的遗传变异，以及Ara-C的药效学目标，将提供一个机会，根据他们的基因图谱识别不良反应风险增加或反应可能性降低的患者，这在未来可能有助于剂量优化，在不影响疗效的情况下减少药物毒性。Ara-C的药物遗传学研究也同样适用于其他核苷类似物，如吉西他滨、地西他滨、氯法拉滨等，它们都是通过相同的途径代谢的。
The mainstay of acute myeloid leukemia chemotherapy is the nucleoside analog cytarabine (ara-C). Numerous studies suggest that the intracellular concentrations of the ara-C active metabolite, ara-CTP, vary widely among patients and, in turn, are associated with variability in clinical response to acute myeloid leukemia treatment. Thus, genetic variation in key genes in the ara-C metabolic pathway – specifically, deoxycytidine kinase (a rate-limiting activating enzyme), 5´ nucleotidase, cytidine deaminase and deoxycytidylate deaminase (all three are inactivating enzymes), human equilibrative nucleoside transporter (ara-C uptake transporter) and ribonucleotide reductase (RRM1 and RRM2 – enzymes regulating intracellular deoxycytidine triphosphate pools) – form the molecular basis of the interpatient variability observed in intracellular ara-CTP concentrations and response to ara-C. Understanding genetic variants in the key candidate genes involved in the metabolic activation of ara-C, as well as the pharmacodynamic targets of ara-C, will provide an opportunity to identify patients at an increased risk of adverse reactions or decreased likelihood of response, based upon their genetic profile, which in future could help in dose optimization to reduce drug toxicity without compromising efficacy. The pharmacogenetic studies on ara-C would also be equally applicable to other nucleoside analogs, such as gemcitabine, decitabine, clofarabine and so on, which are metabolized by the same pathway.
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影响因子：
6.5
作者：
Bhatla D;Gerbing RB;Alonzo TA;Conner H;Ross JA;Meshinchi S;Zhai X;Zamzow T;Mehta PA;Geiger H;Perentesis J;Davies SM
通讯作者：
Davies SM
影响因子：
45.3
作者：
CAPIZZI, RL;YANG, JL;CHENG, YC
通讯作者：
CHENG, YC
DOI：
10.1073/pnas.83.4.986
发表时间：
1986-02-01
影响因子：
11.1
作者：
BIANCHI, V;PONTIS, E;REICHARD, P
通讯作者：
REICHARD, P
影响因子：
6.5
作者：
Galmarini, CM;Thomas, X;Dumontet, C
通讯作者：
Dumontet, C
HIF-1依赖性抑制缺氧中平衡性核苷转运蛋白（ENT）。
DOI：
10.1084/jem.20050177
发表时间：
2005-12-05
期刊：
The Journal of experimental medicine
影响因子：
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作者：
通讯作者：
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