Combining Bevacizumab with Temozolomide Increases the Antitumor Efficacy of Temozolomide in a Human Glioblastoma Orthotopic Xenograft Model
Combining Bevacizumab with Temozolomide Increases the Antitumor Efficacy of Temozolomide in a Human Glioblastoma Orthotopic Xenograft Model
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DOI：
10.1593/neo.08928
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Lefranc, Florence
中科院分区：
文献类型：
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作者：
Mathieu, Veronique;De Neve, Nancy;Lefranc, Florence
目的：本研究的目的是研究慢性替莫唑胺治疗各种胶质瘤模型的体外和体内抗血管生成作用，并证明贝伐单抗（阿瓦斯汀）是否增加了替莫唑胺对胶质瘤的治疗益处。实验设计：采用Western blot法检测替莫唑胺慢性体外治疗后4种胶质瘤细胞系中各种抗血管生成因子的表达水平。用替莫唑胺处理和不处理胶质瘤细胞的上清液孵育人内皮细胞，进行增殖和迁移试验。使用原位胶质瘤模型来评估替莫唑胺在体内的抗血管生成作用，以及单独使用或与贝伐单抗联合使用不同的替莫唑胺治疗方案的治疗效果。结果：替莫唑胺（Temozolomide）是一种促自噬和促凋亡药物，可降低胶质瘤模型中HIF-1 α、ID-1、ID-2和cMyc的表达水平，这些蛋白在血管生成和向缺氧代谢的转变中发挥重要作用。这些变化可能，至少部分地，是体外和体内观察到的血管生成损伤的原因。此外，与单独给药相比，贝伐单抗联合替莫唑胺增加了胶质瘤小鼠的存活率。结论：除了已经确定的替莫唑胺的多种作用机制外，我们在这里报道它还通过损害血管生成过程发挥抗肿瘤作用。我们进一步强调，贝伐单抗是一种具有不同作用机制的抗血管生成药物，可与替莫唑胺联合使用，以增加后者对胶质瘤患者的治疗效果。
PURPOSE: The aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide in glioma. EXPERIMENTAL DESIGN: The expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide. Orthotopic glioma models were used to evaluate the antiangiogenic effects of temozolomide in vivo and the therapeutic benefits of different temozolomide treatment schedules used alone or in combination with bevacizumab. RESULTS: Temozolomide, a proautophagic and proapoptotic drug, decreased the expression levels of HIF-1 alpha, ID-1, ID-2, and cMyc in the glioma models investigated, all of which playing major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be, at least partly, responsible for the impairment of angiogenesis observed in vitro and in vivo. Moreover, combining bevacizumab with temozolomide increased the survival of glioma-bearing mice in comparison to each compound administered alone. CONCLUSIONS: In addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenic processes. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter's therapeutic benefit in glioma patients.