We have shown that solid tumors are angiogenesis-dependent. We have worked out the sequence of steps involved in capillary growth and have shown that the rate of capillary growth can be modulated by fragments of heparin which themselves do not have anticoagulant activity. A new class of corticosteroids which are potent angiogenesis inhibitors in the presence of heparin, but have no other activity, has recently been discovered, and their structure has been elucidated. Two of these compounds are natural metabolites of cortisone which have previously been thought to be biologically inactive. When administered with hexasaccharide fragments of heparin, they inhibit angiogenesis in several in vivo systems, and also act as inhibitors of tumor growth. It appears that these """"""""angiostatic"""""""" steroids contribute to the physiologic suppression of endothelial cell turnover and that tumors must continuously override this sytem to induce angiogenesis. In another set of experiments, the high binding affinity of heparin for endothelial growth factors has permitted us to purify a tumor-derived angiogenic factor. This factor has now been found in mouse tumors, rat tumors, and in the first five human tumors tested. Furthermore, a similar factor has been found in some normal tissues (hypothalamus and brain). It now appears that the major difference between normal and neoplastic tissues is that tumors express these angiogenesis factors continuously, whereas normal tissues rarely express them, and then only under a tightly regulated program. Current work is focused on: (1) animal studies necessary for preparing the angiostatic steroids for clinical trial; and (2) determination of the amino acid sequence of the pure tumor angiogenic factor and production of antibodies against it. (J)
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