Interactions of Multitargeted Kinase Inhibitors and Nucleoside Drugs: Achilles Heel of Combination Therapy?
Interactions of Multitargeted Kinase Inhibitors and Nucleoside Drugs: Achilles Heel of Combination Therapy?
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DOI：
10.1158/1535-7163.mct-14-0337
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发表时间：
2015-01-01
影响因子：
5.7
通讯作者：
Sawyer, Michael B.
中科院分区：
文献类型：
--
作者：
Damaraju, Vijaya L.;Kuzma, Michelle;Sawyer, Michael B.
多靶点酪氨酸激酶抑制剂(TKI)Axitinib、pazopanib和sunitinib被用于治疗许多实体肿瘤。TKIs与一种核苷类抗癌药物吉西他滨在胰腺、肾脏、肺、卵巢和其他恶性肿瘤中的联合试验对患者几乎没有好处。研究了TKI与人核苷转运蛋白(HNT)的相互作用，评价了TKI对重组人核苷转运蛋白(HNT)酵母和培养的人癌细胞株摄取[H-3]尿苷的抑制作用。Axitinib、pazopanib和sunitinib在低微摩尔浓度下抑制hENT1。在A549、ASPC-1和Caki-1细胞中，[H-3]尿苷、[H-3]胸腺嘧啶核苷、[H-3]吉西他滨和[H-3]氟胸苷(Flt)积聚均被三种TKI阻断。Pazopanib>；axitinib>；=sunitinib抑制hENT1的IC50值分别为2、7和29mU·mol/L，导致吉西他滨和Flt在细胞内的积聚减少。TKI对Caki-1细胞的预处理或共处理可减少细胞内[H-3]核苷的积聚，提示TKI与核苷类药物联合应用会影响细胞毒作用。在对Caki-1细胞中顺序和同时添加药物进行比较的联合细胞毒性实验中，当在TKIs之前加入吉西他滨时，细胞毒性最大。在临床环境中，肿瘤组织中TKI抑制剂的浓度足以抑制hENT1的活性，从而降低癌细胞中的核苷化疗药物水平，并降低联合方案的疗效。另外一个不受欢迎的相互作用可能是肿瘤组织中Flt摄取的减少，这可能导致关于肿瘤反应的异常结论。(C)2014年AACR。
Multitargeted tyrosine kinase inhibitors (TKI) axitinib, pazopanib, and sunitinib are used to treat many solid tumors. Combination trials of TKIs with gemcitabine, a nucleoside anticancer drug, in pancreas, renal, lung, ovarian, and other malignancies resulted in little benefit to patients. TKI interactions with human nucleoside transporters (hNT) were studied by assessing inhibition of [H-3] uridine uptake in yeast producing recombinant hNTs individually and in cultured human cancer cell lines. Axitinib, pazopanib, and sunitinib inhibited hENT1 at low micromolar concentrations. In A549, AsPC-1, and Caki-1 cells, [H-3] uridine, [H-3] thymidine, [H-3] gemcitabine, and [H-3] fluorothymidine (FLT) accumulation was blocked by all three TKIs. Pazopanib > axitinib >= sunitinib inhibited hENT1 with IC50 values of 2, 7, and 29 mu mol/L, respectively, leading to reduced intracellular gemcitabine and FLT accumulation. Pretreatment or cotreatment of Caki-1 cells with TKIs reduced cellular accumulation of [H-3] nucleosides, suggesting that TKI scheduling with nucleoside drugs would influence cytotoxicity. In combination cytotoxicity experiments that compared sequential versus simultaneous addition of drugs in Caki-1 cells, cytotoxicity was greatest when gemcitabine was added before TKIs. In clinical settings, TKI inhibitor concentrations in tumor tissues are sufficient to inhibit hENT1 activity, thereby reducing nucleoside chemotherapy drug levels in cancer cells and reducing efficacy in combination schedules. An additional unwanted interaction may be reduced FLT uptake in tumor tissues that could lead to aberrant conclusions regarding tumor response. (C) 2014 AACR.