Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement
Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement
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DOI：
10.1016/j.canlet.2008.02.018
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发表时间：
2008-06-28
期刊：
影响因子：
9.7
通讯作者：
Sone, Saburo
中科院分区：
文献类型：
--
作者：
Ogino, Hirokazu;Yano, Seiji;Sone, Saburo
恶性胸膜间皮瘤（MPM）是一种侵袭性强、预后差的恶性肿瘤，因此迫切需要开发新的有效治疗方法。在本研究中，我们在原位MPM模型中研究了凡德他尼（ZD 6474）（一种VEGFR-2、EGFR和RET酪氨酸激酶抑制剂）的治疗疗效。我们发现人MPM细胞系EHMES-10表达RET/PTC 3致癌重排和大量VEGF。Vandetanib在体外诱导EHMES-10细胞凋亡并抑制其增殖（IC 50 = 0.3 μ M）。每日一次口服凡德他尼可抑制肿瘤血管生成，并显著减少胸部肿瘤的生长和胸腔积液的产生，从而延长EHMES-10正向移植模型中小鼠的存活时间。相反，选择性EGFR酪氨酸激酶抑制剂吉非替尼在体外和体内对EHMES-10细胞均无作用。我们的研究结果表明，使用凡德他尼靶向RET依赖性肿瘤细胞增殖和存活以及VEGFR-2依赖性肿瘤血管生成可能有希望对抗表达RET致癌重排和VEGF的MPM。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, therefore development of novel effective therapies is urgent. In the present study, we investigated the therapeutic efficacy of vandetanib (ZD6474), an inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, in an orthotopic model of MPM. We found that a human MPM cell line, EHMES-10, expressed RET/PTC3 oncogenic rearrangement and a large amount of VEGF. Vandetanib induced the apoptosis and inhibited the proliferation of EHMES-10 cells ill Vitro (IC50 = 0.3 mu M). Once-daily oral treatment with vandetanib inhibited tumor angiogenesis, and reduced significantly the growth of thoracic tumors and the production of pleural effusions, resulting in the prolonged survival of mice in EHMES-10 orthograft model. In contrast, the selective EGFR tyrosine kinase inhibitor, gefitinib, had no effect against EHMES-10 cells both in vitro and in vivo. Our results suggest that using vandetanib to target RET-dependent tumor cell proliferation and survival and VEGFR-2-dependent tumor angiogenesis may be promising against MPM expressing RET oncogenic rearrangement and VEGF. (C) 2008 Elsevier Ireland Ltd. All rights reserved.