Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU
Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU
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DOI：
10.1002/cmdc.201000447
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发表时间：
2011-03-07
期刊：
影响因子：
3.4
通讯作者：
Kirstein, Mark N.
中科院分区：
文献类型：
--
作者：
Benyumov, Alexey;Gurvich, Vadim J.;Kirstein, Mark N.
最近的证据表明吉西他滨代谢物 dFdU 具有药理活性。尽管效力较低，但 dFdU 的半衰期较长，可以增强或拮抗吉西他滨的活性。因此，进行了研究来评估综合效果。化学合成后，开发了一种改进的 dFdU 纯化程序（产率 80%；纯度 > 99%）。基于斑马鱼表型的胚胎筛选显示，吉西他滨或 dFdU 治疗后没有急性毒性。只有吉西他滨以剂量依赖性方式影响斑马鱼的发育。没有观察到组合的协同作用或拮抗作用。 dFdU 的抗肿瘤作用呈剂量依赖性。拮抗作用是肿瘤细胞系依赖性的，并且不依赖于吉西他滨细胞内活性代谢物的形成，这表明药物-代谢物相互作用发生得较晚。这些研究突出了测试抗癌剂和代谢物组合的药理活性的平台。此类分析有望深入了解代谢物对母体药物活性的有益或有害影响。
Recent evidence has shown that the gemcitabine metabolite, dFdU, is pharmacologically active. Though less potent, dFdU has a longer half-life and could potentiate or antagonize the activity of gemcitabine. Hence, studies were undertaken to evaluate the combined effects. Following chemical synthesis, an improved purification procedure for dFdU was developed (80% yield; > 99% purity). Zebrafish phenotype-based embryo screens revealed no acute toxicity after gemcitabine or dFdU treatment. Only gemcitabine affected zebrafish development in a dose-dependent manner. Synergy or antagonism for the combination was not observed. Antitumor effects for dFdU were dose dependent. Antagonism was tumor cell-line dependent and did not depend on formation of the intracellular active metabolite of gemcitabine, suggesting that the drug-metabolite interaction occurs later. These studies highlight a platform for testing the pharmacologic activity for anticancer agent and metabolite combinations. Such analyses are expected to provide insight into the beneficial or harmful effect(s) of metabolites towards parent drug activity.