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首页> 外文期刊>Clinical cancer research: an official journal of the American Association for Cancer Research >Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity
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Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity

机译：厄洛替尼，吉非替尼和vandetanib抑制人核苷转运蛋白并保护癌细胞免受吉西他滨的细胞毒性

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Purpose: Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides. Experimental Design: TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines. Results: Erlotinib, gefitinib and vandetanib inhibited [3H]uridine transport in yeast and [3H]uridine and [3H]gemcitabine uptake in the four cell lines. Treatment of cell lines with erlotinib, gefitinib, or vandetanib for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth. Conclusions: Vandetanib inhibited hENT1, hENT2, hCNT1, hCNT2, and hCNT3, whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1. The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination. Clin Cancer Res; 20(1); 176-86.
机译：目的：已尝试将酪氨酸激酶抑制剂（TKI）与吉西他滨组合使用，对患者几乎没有增加益处。我们假设设计为与生长因子受体的ATP结合袋结合的TKI也与识别核苷的转运蛋白结合。实验设计：用酵母中单独产生的重组人（h）平衡（E）和浓缩（C）核苷转运蛋白（hENT，hCNT）研究了TKI对尿苷转运的抑制作用。在人胰腺和肺癌细胞系中评估了TKI对尿苷转运，吉西他滨积累，hENT1活性的调节以及吉西他滨存在或不存在下细胞活力的影响。结果：厄洛替尼，吉非替尼和vandetanib抑制了酵母中的[3H]尿苷转运，并抑制了这四个细胞系中的[3H]尿苷和[3H]吉西他滨摄取。用埃洛替尼，吉非替尼或vandetanib处理细胞系24小时降低了hENT1活性，随后在无药培养基中孵育24小时将其逆转。吉西他滨在厄洛替尼，吉非替尼或vandetanib之前给药比在同时给药时观察到更大的细胞毒性，并且在三种细胞系中观察到使用CalcuSyn Software评估的协同作用，导致联合指数低于0.6，细胞生长减少了50％。结论：Vandetanib抑制hENT1，hENT2，hCNT1，hCNT2和hCNT3，而厄洛替尼抑制hENT1和hCNT3，吉非替尼抑制hENT1和hCNT1。由于TKI对hENTs和/或hCNTs的抑制作用，导致肿瘤组织中核苷化学治疗药物蓄积减少的可能性表明，在联合计划TKI和核苷化学治疗时，必须考虑这些药物的药代动力学特性。临床癌症研究; 20（1）; 176-86。

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