Aviles Ronnier J, Annex Brian H, Lederman Robert J
The Cardiovascular Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2C713, MSC 1538, Bethesda, MD 20892-1538, USA.
Br J Pharmacol. 2003 Oct;140(4):637-46. doi: 10.1038/sj.bjp.0705493.
Therapeutic angiogenesis represents an attempt to relieve inadequate blood flow by the directed growth and proliferation of blood vessels. Neovascularization is a complex process involving multiple growth factors, receptors, extracellular matrix glycoproteins, intracellular and extracellular signaling pathways, and local and bone-marrow-derived constituent cells, all responding to a symphonic arrangement of temporal and spatial cues. In cardiovascular disease, patients with refractory angina and lower extremity intermittent claudication seem most amenable to early tests of therapeutic angiogenesis. Monotherapy with the recombinant protein basic fibroblast growth factor (FGF-2) has been tested in six human trials. These have shown provisional safety, and two have provided 'proof of concept' for the strategy of therapeutic angiogenesis. One large randomized phase II trial failed to show significant efficacy in coronary artery disease. Another showed significant efficacy in peripheral artery disease, although the magnitude of benefit was disappointing at the dose tested. This overview details the suitable clinical trial design and further steps toward the clinical development of FGF-2.
治疗性血管生成旨在通过引导血管生长和增殖来缓解血流不足。新生血管形成是一个复杂的过程，涉及多种生长因子、受体、细胞外基质糖蛋白、细胞内和细胞外信号通路，以及局部和骨髓来源的组成细胞，所有这些都对时空线索的协同排列做出反应。在心血管疾病中，难治性心绞痛和下肢间歇性跛行患者似乎最适合早期治疗性血管生成试验。重组蛋白碱性成纤维细胞生长因子（FGF-2）的单一疗法已在六项人体试验中进行了测试。这些试验显示了初步安全性，其中两项为治疗性血管生成策略提供了“概念验证”。一项大型随机II期试验未能显示在冠状动脉疾病中有显著疗效。另一项试验显示在周围动脉疾病中有显著疗效，尽管在所测试的剂量下获益程度令人失望。本综述详细介绍了合适的临床试验设计以及FGF-2临床开发的进一步步骤。
