| Research Abstract |
The present study provided the following four lines of evidence. First, 3 isoforms of platelet-derived growth factor, whose membrane receptors contain functional tyrosine kinase domains, are all indirect inducers of angiogenesis in vivo. Second, we previously showed that herbimycin A,a microbial tyrosine kinase inhibitor, is a potent inhibitor of angiogenesis using an in vivo assay system involving chorioallantoic membranes (CAMs) of growing chick embryos. The present experiment identified functional groups responsible for the antiangiogenic effect of herbimycin A under the same assay conditions. Third, based on our previous findings that eponemysin and radicicol, epoxide-containing microbial products, inhibit angiogenesis in a CAM assay system, we have a working hypothesis that the epoxide group will be a useful indicator in the search for novel angiogenesis inhibitors. As the first attempt to verify this, in vivo experiments were conducted to determine whether rhizoxin, amicrobial metabolite containing two epoxide groups, affects angiogenesis in a CAM or mouse dorsal air sac assay system. It was found to be a potent inhibitor of angiogenesis in both assay systems. Depudecin, another epoxide-containing microbial product, also has antiangiogenic activity. Finally, cytogenin, a microbial product, was found to have antitumor and anti-rheumatoid arthritis effects, but its mechanism of action was not fully established. We assumed that the inhibitory effects of cytogenin on these two diseases involve its antiangiogenic activity, because the two diseases are well-known to be angiogenic disorders. The microbial product had no effect on embryonic angiogenesis, but significantly affected tumor angiogenesis even when administered orally.
Based on these findings, we proposed that angiogenesis is an important target for overcoming angiogenesis-dependent diseases, including cancer, diabetic retinopathy and rheumatoid arthritis.
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