Type IV collagenase inhibitor as an angiogenic inhibitor

血管生成，即新生血管，不仅是正常生理过程中的一种重要现象，而且在慢性炎症和肿瘤形成等疾病状态下也是一种必不可少的现象。许多报道表明，血管生成对于实体瘤的进行性生长和原发部位转移瘤的脱落具有重要意义。因此，血管生成的抑制可能导致肿瘤的生长受到抑制。血管生成通过一系列事件发生，包括血管生成因子(S)激活内皮细胞、酶降解基底膜、毛细血管内皮细胞迁移、增殖和毛细血管内皮细胞形成管状结构。多种蛋白水解酶与血管生成有关，胶原酶和纤溶酶原激活剂在基底膜的降解中起重要作用。然而，体内血管生成的主导酶还不是很清楚。…的澄清更多的血管生成关键酶及其特异性抑制剂可能会导致寻找有效的血管生成抑制剂，也可能通过抑制血管生成来调节肿瘤的生长和转移。此前，我们检测了低分子蛋白酶抑制剂对CAM血管生成的影响，以阐明体内血管生成过程中的关键酶，发现放线菌素是一种血管生成抑制物。我们还利用毛细血管内皮细胞研究了放线菌素抑制血管生成的机制，提示放线菌素通过抑制IV型胶原酶抑制血管生成，该酶是血管生成中的优势酶。在本研究中，我们试图利用放线菌素及其衍生物来检测抑制IV型胶原酶的能力和抑制血管生成的能力之间的相关性，以确定该酶活性是否对血管生成重要。这两种活动是相关的。我们还检测了放线菌素的抗肿瘤活性。放线菌素抑制肿瘤对宿主的摄取。这些结果表明：1)IV型胶原酶是血管生成的主导酶，2)抑制IV型胶原酶导致血管生成抑制，3)IV型胶原酶较少

Angiogenesis, neovascularization, is an essential phenomenon not only in normal physiological process, but also in some disease states such as chronic inflammation and tumor formation. Many reports have shown the importance of angiogenesis for the progressive growth of solid tumors and the shedding of metastatic tumors from the primary sites. So the inhibition of angiogenesis may cause the suppression of tumor growth. Angiogenesis occurs via a copmlex cascade of events including activation of endothelial cells by angiogenic factor(s), degradation of the basement membrane by enzymes, migration, proliferation of capillary endothelial cells and tube formation by capillary endothelial cells. A variety of proteases have been implicated in angiogenesis, and collagenase and plasminogen activator have been suggested to play the important roles in degradation of the basement membrane. However, the dominant enzyme in angiogenesis in vivo has not been elucidated clearly. The clarification of the … More key enzymes in angiogenesis and their specific inhibitors may lead to search for potent inhibitors of angiogenesis, and may also lead to the regulation of tumor growth and metastasis through the inhibition of angiogenesis.Previously, we examined the effects of low molecular weight protease inhibitors on the angiogenesis of CAM to clarify the key enzyme during angiogenesis in vivo and found actinonin as a angiogenic inhibitor. We also examined theinhibitory mechanism of actinonin on angiogenesis, using capillary endothelial cells, and suggested that actinonin inhibited angiogenesis through the inhibition of type IV collagenase and that this enzyme was adominant enzyme in angiogenesis.In this study, we attempted to examine the correlation between the ability of the inhibition of type IV collagenase and angiogenesis inhibition, using actinonin and its derivatives, to determine whether this enzyme activity was important to angiogenesis. Both activities were correlative. We also examined the antitumor activity of actinonin. Actinonin inhibited the tumor uptake to the host. These results indicated that 1) type IV collagenase was a dominant enzyme in angiogenesis, 2) inhibition of type IV collagenase led to the angiogenesis inhibition and 3) type IV collagenase Less