Type IV collagenase inhibitor as an angiogenic inhibitor

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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