The development of potent anti-angiogenic compounds offers great therapeutic potential in "angiogenesis-dependent diseases" that show uncontrolled growth of capillary blood vessels. A group of steroids are reported to inhibit angiogenesis in the presence of heparin. The list of steroids showing anti-angiogenic activity has been expanded by preliminary data from our laboratory to include corticoid metabolites, including the glucuronides. We postulate that these steroid metabolite-heparin combinations inhibit angiogenesis by enhancing capillary basal membrane turnover and endothelial cell rounding. We believe that this anti- angiogenic activity can be enhanced and propose several synthetically derived steroids as potent inhibitors of angiogenesis. A major focus of this study will be to determine the anti- angiogenic index for a number of steroid metabolites, both natural and synthetic. Special emphasis will be placed on determining the anti-angiogenic index for additional steroid conjugates, especiallY glucuronides. The steroids and steroid conjugates will be initially tested in the chick chorioallantoic membrane assay (CAM) for their ability to inhibit angiogenesis. Selected compounds that show activity will be tested for their ability to inhibit tumorigenesis and cause regression of tumor load using the Lewis lung carcinoma in the C57BL/6 mouse. Using the information from these experiments, we will develop a structure-function relationship for the anti-angiogenic activity of steroids and steroid metabolites. Special emphasis will be placed on developing synthetic derivatives that show anti- angiogenic activity without heparin.