Bikfalvi Andreas
Molecular Mechanisms of Angiogenesis Laboratory (INSERM E0113), Université Bordeaux I, Avenue des Facultés, 33 405 Talence, France.
Biochem Pharmacol. 2004 Sep 15;68(6):1017-21. doi: 10.1016/j.bcp.2004.05.030.
Inhibition of angiogenesis is an important strategy to block tumor growth and invasion. We discuss herein results from our ongoing investigations on platelet factor-4 (PF-4) and the VEGF/VEGFR system. Platelet factor-4 (PF-4) is an anti-angiogenic ELR-negative chemokine. PF-4 inhibits endothelial cell proliferation and migration, and angiogenesis in vitro and in vivo. We have studied the structure and anti-angiogenic activities of a C-terminal fragment of PF-4 named PF-4 CTF. This molecule retains anti-angiogenic activity, blocks the interaction of angiogenesis factors with their receptors and may also be improved by mutation or domain-swapping. It seems, therefore, to be a good candidate for further development. Furthermore, we have developed a cyclic vascular endothelial growth inhibitor (Cyclo VEGI) from the structure of VEGF-A. In aqueous solution, cyclo-VEGI adopts an alpha helix conformation. Cyclo-VEGI inhibits binding of iodinated VEGF(165) to endothelial cells and angiogenesis. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival.
抑制血管生成是阻断肿瘤生长和侵袭的重要策略。我们在此讨论我们对血小板因子-4（PF-4）和VEGF/VEGFR系统正在进行的研究结果。血小板因子-4（PF-4）是一种抗血管生成的ELR阴性趋化因子。PF-4在体外和体内均可抑制内皮细胞增殖、迁移及血管生成。我们研究了PF-4的一个C末端片段PF-4 CTF的结构和抗血管生成活性。该分子保留了抗血管生成活性，阻断血管生成因子与其受体的相互作用，并且还可通过突变或结构域交换进行改进。因此，它似乎是进一步开发的良好候选物。此外，我们基于VEGF-A的结构开发了一种环状血管内皮生长抑制剂（Cyclo VEGI）。在水溶液中，Cyclo-VEGI呈α螺旋构象。Cyclo-VEGI可抑制碘化VEGF(165)与内皮细胞的结合及血管生成。此外，Cyclo-VEGI可显著阻断裸鼠和同基因小鼠中已形成的颅内胶质瘤的生长并提高生存率。
