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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >A phase 1 comparative pharmacokinetic and cardiac safety study of two intravenous formulations of CO-101 in patients with advanced solid tumors
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A phase 1 comparative pharmacokinetic and cardiac safety study of two intravenous formulations of CO-101 in patients with advanced solid tumors

机译：两种CO-101静脉内制剂对晚期实体瘤患者的1期比较药代动力学和心脏安全性研究

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CO-101 (also known as CP-4126, Supplementary Figure S1) is a gemcitabine (2′,2′-difluorodeoxycytidine; dFdC) elaidic acid ester, developed to improve the clinical activity of dFdC.[1] dFdC is a nucleoside analogue and used in the treatment of patients with various solid tumors.[2] dFdC is an hydrophilic compound, that needs to be transported into the cells by human equilibrative and concentrative nucleoside transporters (hENT and hCNT) to exert its anticancer activity with hENT1 being the primary transporter.[3] A growing body of literature has shown that tumors with low levels of hENT1 respond poorly to nucleoside analogues.[4, 5] Moreover, a mechanism of resistance to dFdC is a decreased transport activity of nucleosides over the cell membrane.[3, 6, 7] By the esterification of the 5′ position of dFdC with an elaidic fatty acid (trans-9-octadecenoic fatty acid), CO-101 can traverse cell membranes by passive diffusion, followed by intracellular conversion to dFdC (Supplementary Figure S2). This means that uptake of CO-101 in the cell is independent of nucleoside transporters and might be more effective in patients with low levels of hENT1 in tumors.[8-10] Since hENT1 can operate as uptake as well as export transporter, the clinical activity could be improved by cellular accumulation
机译：CO-101（也称为CP-4126，补充图S1）是吉西他滨（2'，2'-二氟脱氧胞苷; dFdC）的花生酸酯，旨在提高dFdC的临床活性。[1] dFdC是一种核苷类似物，用于治疗各种实体瘤患者。[2] dFdC是一种亲水性化合物，需要通过人类平衡和集中核苷转运蛋白（hENT和hCNT）转运到细胞中，才能发挥其抗癌活性，而hENT1是主要转运蛋白。[3]越来越多的文献表明，hENT1水平低的肿瘤对核苷类似物的反应较差。[4，5]此外，对dFdC的抗性机制是核苷在细胞膜上的转运活性降低。[3，6， [图7]通过将dFdC的5'位与桉树油脂肪酸（反式-十八-十八烯脂肪酸）酯化，CO-101可以通过被动扩散而穿过细胞膜，然后细胞内转化为dFdC（补充图S2）。这意味着细胞中CO-101的吸收与核苷转运蛋白无关，并且在肿瘤中hENT1水平低的患者中可能更有效。[8-10]由于hENT1既可以作为吸收转运蛋白，也可以作为转运转运蛋白，因此临床上细胞积累可以改善活性

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