We previously identified the angiogenesis inhibitor angiostatin. Using a similar strategy, we have identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin specifically inhibits endothelial proliferation and potently inhibits angiogenesis and tumor growth. By a novel method of sustained release, E. coli-derived endostatin was administered as a nonrefolded suspension. Primary tumors were regressed to dormant microscopic lesions. Immunohistochemistry revealed blocked angiogenesis accompanied by high proliferation balanced by apoptosis in tumor cells. There was no toxicity. Together with angiostatin data, these findings validate a strategy for identifying endogenous angiogenesis inhibitors, suggest a theme of fragments of proteins as angiogenesis inhibitors, and demonstrate dormancy therapy.
Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of aniogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antaniogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization ofthafidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally adminsered drug for the treatment of many diverse dease dependent on angiogenesis.Thalidomide is a potent teratogen. It was developed by Chemie Grunenthal in the 1950s as a sedative that appeared so nontoxic in rodent models that a LD50 could not be established. In 1961, McBride (1) and Lenz (2) described the association between limb defects in babies and maternal thalidomide usage. Although humans are exquisitely sensitive to the teratogenic effects of thalidomide, experiments in rodents failed to reveal similar effects (3, 4). Teratogenic effects could be experimentally reproduced by the administration of thalidomide to pregnant rabbits at an oral dose of 100-300 mg per kg per day (5, 6). Over the past 30 years, the mechanism of thalidomide's teratogenicity has been extensively studied but has remained unsolved (7).We now postulate that the limb defects seen with thalidomide were secondary to an inhibition of blood vessel growth in the developing fetal limb bud. The limb bud is unique in requiring a complex interaction of both angiogenesis and vasculogenesis during development (8). Vasculogenesis is the formation of a capillary bed from endothelial cells that have differentiated from mesenchymal precursors. Angiogenesis is the formation of new blood vessels from sprouts ofpreexisting vessels. Therefore, the limb bud would be a particularly vulnerable target to a teratogen that inhibited endothelial cell function. We chose to examine the effect of thalidomide on growing vasculature in the chicken chorioallantoic membrane and in the rabbit cornea. MATERIALS AND METHODSChicken chorioallantoic membrane (CAM) assays were performed as described (9, 10) and the effects on the developing vasculature were recorded at 48 h after implantation of the 0.5% carboxymethylcellulose pellet containing various drugs. Corneal
Background-Neovascularization within the intima of human atherosclerotic lesions is well described, but its role in the progression of atherosclerosis is unknown. In this report, we first demonstrate that intimal vessels occur in advanced lesions of apolipoprotein E-deficient (apoE Ϫ/Ϫ) mice. To test the hypothesis that intimal vessels promote atherosclerosis, we investigated the effect of angiogenesis inhibitors on plaque growth in apoE Ϫ/Ϫ mice. Methods and Results-ApoE Ϫ/Ϫ mice were fed a 0.15% cholesterol diet. At age 20 weeks, mice were divided into 3 groups and treated for 16 weeks as follows: group 1, recombinant mouse endostatin, 20 mg ⅐ kg Ϫ1 ⅐ d
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