Bevacizumab and Ranibizumab on Microvascular Endothelial Cells: A Comparative Study
Bevacizumab and Ranibizumab on Microvascular Endothelial Cells: A Comparative Study
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DOI：
10.1002/jcb.22378
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发表时间：
2009-12-15
影响因子：
4
通讯作者：
Soares, Raquel
中科院分区：
文献类型：
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作者：
Costa, Raquel;Carneiro, Angela;Soares, Raquel
由于其在血管内皮细胞中的广泛作用，血管内皮生长因子(VEGF)是血管生成的主要限速步骤。因此，血管内皮生长因子的靶向治疗很快被开发出来。贝伐单抗和雷尼贝珠单抗是其中两种已经在临床使用的治疗剂。贝伐单抗最初用于癌症治疗，而雷尼比珠单抗设计用于治疗脉络膜新生血管，脉络膜新生血管是老年性黄斑变性失明的主要原因。本研究旨在比较贝伐单抗和雷尼比单抗对人微血管内皮细胞(HMECs)的多重作用。培养人脐静脉内皮细胞，在24 h内加入玻璃体内浓度范围内的抗血管内皮生长因子药物或辅料。检测细胞培养液中血管内皮生长因子含量和细胞裂解液中血管内皮生长因子受体2(VEGFR-2)的表达。在任何浓度的抗血管内皮生长因子处理的培养物中均未发现细胞毒性(MTS法)。两种药物孵育后，细胞凋亡率(TUNEL法)显著增加，细胞增殖(BrdU法)、迁移(Transwell法)和向血管结构的组装均显著降低。伴随着这些发现的是，在临床浓度下，两种药物的血管内皮生长因子释放和磷酸化的VEGFR-2和Akt表达都显著减少。有趣的是，磷酸化的ERK只有在贝伐单抗治疗后才显著减少。此外，与雷尼比珠单抗相比，贝伐单抗对细胞增殖的影响更大，而迁移、毛细血管形成和磷酸化的VEGFR2表达显著减少。因此，虽然两种药物都有抗血管生成的作用，但这两种分子在HMEC中发挥了不同的作用。这些发现表明，在临床环境中对这些影响进行仔细的确认是强制性的。J.细胞。生物化学。108：1410-1417,2009。(C)2009年Wiley-Liss，Inc.
Given its broad effects in endothelium, vascular endothelial growth factor (VEGF) represents the primary rate-limiting step of angiogenesis. Therefore, VEGF targeting therapies were soon developed. Bevacizumab and ranibizumab are two of these therapeutic agents already in clinical use. Bevacizumab was first used for cancer treatment, whereas ranibizumab was designed to target choroidal neovascularization, the main cause of blindness in age-related macular degeneration. The present study aims to compare the multiple effects of bevacizumab and ranibizumab in human microvascular endothelial cells (HMECs). HMEC cultures were established and treated during 24 h with the anti-VEGF agents within the intravitreal-established concentration range or excipients. Analyses of VEGF content in cell media and VEGF receptor-2 (VEGFR-2) expression in cell lysates were performed. No cell cytotoxicity (MTS assay) was found in anti-VEGF-treated cultures at any concentration. Apoptosis (TUNEL assay) was significantly increased and cell proliferation (BrdU assay), migration (transwell assay) and assembly into vascular structures were significantly reduced by incubation with both agents at the two doses used. These findings were accompanied by a strong decrease in VEGF release, and in phosphorylated VEGFR-2 and Akt expression for both agents at the clinical concentration. Interestingly, phosphorylated Erk was only significantly reduced upon bevacizumab treatment. In addition, proliferation was more affected by ranibizumab, whereas migration, capillary formation, and phosphorylated VEGFR2 expression were significantly reduced by bevacizumab as compared to ranibizumab. Therefore, although both agents presented anti-angiogenic actions, distinct effects were exerted by the two molecules in HMEC. These findings suggest that a careful confirmation of these effects in clinical settings is mandatory. J. Cell. Biochem. 108: 1410-1417, 2009. (C) 2009 Wiley-Liss, Inc.