Vandetanib mediates anti-leukemia activity by multiple mechanisms and interacts synergistically with DNA damaging agents.
Vandetanib mediates anti-leukemia activity by multiple mechanisms and interacts synergistically with DNA damaging agents.
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DOI：
10.1007/s10637-010-9572-6
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发表时间：
2012-04
影响因子：
3.4
通讯作者：
Gore, Lia
中科院分区：
文献类型：
--
作者：
Macy, Margaret E.;DeRyckere, Deborah;Gore, Lia
关键词：
凡德他尼是一种口服活性小分子酪氨酸激酶抑制剂（TKI），对恶性肿瘤中涉及的几种途径具有活性，包括血管内皮生长因子受体途径、表皮生长因子受体途径、血小板衍生生长因子受体β途径和转染过程中的重排途径。为了确定凡德他尼介导的受体酪氨酸激酶抑制是否是儿科急性白血病的潜在治疗策略，这些研究旨在表征凡德他尼对急性白血病的体外活性。用凡德他尼处理白血病细胞系导致增殖和存活率呈剂量依赖性降低。Vandetanib的抗白血病活性似乎是由多种机制介导的，包括在较低浓度下在G1期的蓄积和在较高浓度下的凋亡。凡德他尼处理也发生了细胞表面标志物的改变，表明诱导分化。与DNA损伤剂（依托泊苷和多柔比星）联合使用时，凡德他尼表现出协同诱导细胞死亡。然而，与抗代谢物甲氨蝶呤联合使用时，凡德他尼对细胞死亡具有拮抗作用。尽管急性白血病细胞系上表达了几种凡德他尼靶点，但凡德他尼靶点的表达并不能预测凡德他尼的敏感性，因此单独的凡德他尼靶点不太可能是急性白血病患者的候选生物标志物。凡德他尼和标准化疗药物之间的体外相互作用可能有助于指导复发/难治性急性白血病患者在临床环境中进一步评价联合方案的选择。总之，这些临床前数据支持凡德他尼联合细胞毒性化疗治疗儿童白血病的临床评价。
Vandetanib is an orally active small molecule tyrosine kinase inhibitor (TKI) with activity against several pathways implicated in malignancy including the vascular endothelial growth factor receptor pathway, the epidermal growth factor receptor pathway, the platelet derived growth factor receptor β pathway, and REarranged during Transfection pathway. To determine if vandetanib-mediated inhibition of receptor tyrosine kinases is a potential therapeutic strategy for pediatric acute leukemia, these studies aimed to characterize the activity of vandetanib against acute leukemia in vitro. Treatment of leukemia cell lines with vandetanib resulted in a dose-dependent decrease in proliferation and survival. Vandetanib’s anti-leukemic activity appeared mediated by multiple mechanisms including accumulation in G1 phase at lower concentrations and apoptosis at higher concentrations. Alterations in cell surface markers also occurred with vandetanib treatment, suggesting induction of differentiation. In combination with DNA damaging agents (etoposide and doxorubicin) vandetanib demonstrated synergistic induction of cell death. However in combination with the anti-metabolite methotrexate, vandetanib had an antagonistic effect on cell death. Although several targets of vandetanib are expressed on acute leukemia cell lines, expression of vandetanib targets did not predict vandetanib sensitivity and alone are therefore not likely candidate biomarkers in patients with acute leukemia. Interactions between vandetanib and standard chemotherapy agents in vitro may help guide choice of combination regimens for further evaluation in the clinical setting for patients with relapsed/refractory acute leukemia. Taken together, these preclinical data support clinical evaluation of vandetanib, in combination with cytotoxic chemotherapy, for pediatric leukemia.
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影响因子：
30.8
作者：
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通讯作者：
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