Vandetanib restores head and neck squamous cell carcinoma cells' sensitivity to cisplatin and radiation in vivo and in vitro.
Vandetanib restores head and neck squamous cell carcinoma cells' sensitivity to cisplatin and radiation in vivo and in vitro.
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DOI：
10.1158/1078-0432.ccr-10-2120
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发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Myers JN
中科院分区：
文献类型：
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作者：
Sano D;Matsumoto F;Valdecanas DR;Zhao M;Molkentine DP;Takahashi Y;Hanna EY;Papadimitrakopoulou V;Heymach J;Milas L;Myers JN
我们研究了凡德他尼（一种血管内皮生长因子受体-2（VEGFR-2）、表皮生长因子受体（EGFR）和转染期间重排（RET）酪氨酸激酶活性的抑制剂）是否可以在人头颈部鳞状细胞癌（HNSCC）的临床前体外和体内模型中增强放射联合或不联合顺铂的抗肿瘤活性。使用原位裸鼠模型，在体外和体内单独或联合使用凡德他尼、顺铂和放射处理顺铂和放射抗性的OSC-19和HN 5 HNSCC细胞。使用克隆形成存活测定、肿瘤体积、生物发光成像、肿瘤生长延迟、存活、微血管密度、肿瘤和内皮细胞凋亡以及EGFR和Akt磷酸化数据评估治疗效果。凡德他尼联合顺铂放射增敏HNSCC细胞的体外和体内研究。凡德他尼、顺铂和放疗的联合治疗在体内抗肿瘤作用、延长生存期、减少颈淋巴结转移方面优于其余治疗（包括双重组合）。它还增加了肿瘤和肿瘤相关的内皮细胞凋亡，并降低体内微血管密度。对肿瘤生长延迟数据的分析显示，凡德他尼联合顺铂增强了体内放射反应。所有含凡德他尼的治疗在体外和体内均抑制EGFR和Akt磷酸化。在体外和体内HNSCC模型中，将凡德他尼添加到顺铂和放射的联合治疗中能够有效克服顺铂和放射抗性。可能需要在临床试验中对该方案进行进一步研究。
We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC). OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data. Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo. The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted.