State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Mol Ther. 2012 May;20(5):938-47. doi: 10.1038/mt.2011.285. Epub 2012 Jan 24.
The binding of vascular endothelial growth factor (VEGF) to its receptors stimulates tumor growth; therefore, modulation of VEGF would be a viable approach for antiangiogenic therapy. We constructed a series of soluble decoy receptors containing different VEGF receptor 1 (FLT1) and VEGF receptor 2 (KDR) extracellular domains fused with the Fc region of human immunoglobulin (Ig) and evaluated their antiangiogenic effects and antitumor effects. Results of in vitro binding and cell proliferation assays revealed that decoy receptor FP3 had the highest affinity to VEGF-A and -B. Compared with bevacizumab, FP3 more effectively inhibited human umbilical vein endothelial cell (HUVEC) migration and vessel sprouting from rat aortic rings. FP3 significantly reduced phosphorylation of AKT and ERK1/2, critical proteins in the VEGF-mediated survival pathway in endothelial cells. Moreover, FP3 inhibited tumor growth in human hepatocellular carcinoma (HepG2), breast cancer (MCF-7), and colorectal cancer (LoVo) tumor models, and reduced microvessel density in tumor tissues. The FP3-mediated inhibition of tumor growth was significantly higher than that of bevacizumab at the same dose. FP3 also demonstrated synergistic antitumor effects when combined with 5-fluorouracil (5-FU). Taken together, FP3 shows a high affinity for VEGF and produced antiangiogenic effects, suggesting its potential for treating angiogenesis-related diseases such as cancer.
血管内皮生长因子（VEGF）与其受体的结合会刺激肿瘤生长；因此，VEGF 的调节可能是抗血管生成治疗的一种可行方法。我们构建了一系列含有不同 VEGF 受体 1（FLT1）和 VEGF 受体 2（KDR）胞外结构域的可溶性诱饵受体，与人类免疫球蛋白（Ig）的 Fc 区融合，并评估了它们的抗血管生成作用和抗肿瘤作用。体外结合和细胞增殖试验的结果表明，诱饵受体 FP3 与 VEGF-A 和 -B 的亲和力最高。与贝伐单抗相比，FP3 更有效地抑制了人脐静脉内皮细胞（HUVEC）的迁移和大鼠主动脉环中的血管发芽。FP3 显著抑制了内皮细胞中 VEGF 介导的生存途径中的 AKT 和 ERK1/2 的磷酸化。此外，FP3 抑制了人肝癌（HepG2）、乳腺癌（MCF-7）和结直肠癌（LoVo）肿瘤模型中的肿瘤生长，并降低了肿瘤组织中的微血管密度。在相同剂量下，FP3 介导的肿瘤生长抑制作用明显高于贝伐单抗。FP3 与 5-氟尿嘧啶（5-FU）联合使用时也表现出协同的抗肿瘤作用。总之，FP3 对 VEGF 具有高亲和力并产生抗血管生成作用，表明其在治疗与血管生成相关的疾病（如癌症）方面具有潜力。
