For tumors to grow and metastasize, they induce the generation of new blood vessels, a process referred to as angiogenesis. Inhibition of angiogenesis is thus an attractive approach to inhibit, cancer growth and metastasis. The angiogenesis inhibitor angiostatin is a kringle containing internal fragment of plasminogen, which has been shown to inhibit cancer growth in numerous animal models. In preliminary research, we have demonstrated the mechanism of generation of native human angiostatin, yielding an isoform referred to as Angiostatin4.5 (AS4.5) [Appendices A, B, C]. Plasminogen is first converted to plasmin by a plasminogen activator, and in the presence of a free sulfhydryl donor, plasmin undergoes auto-proteolysis to yield AS4.5 Furthermore, we have shown that AS4.5 is present in plasma and other human specimens, and native AS4.5 is a potent angiogenesis and tumor inhibitor. In more recent experiments, we have now observed that AS4.5 circulates both as a monomer as well as in a complex with as yet undefined other proteins. Furthermore, in experiments in mice, and in human cancer patients administration of an """"""""Angiostatic Cocktail,"""""""" consisting of a plasminogen activator and a free sulfhydryl donor, resulted in marked increases in plasma levels of monomeric and complexed AS4.5 Administration of the Angiostatic Cocktail suppressed EOMA (hemangioendothelioma) tumors >95% in mice. In pilot experiments with patients with cancer, administration of an Angiostatic Cocktail resulted in increased plasma levels of AS4.5 from approximately 5 nM to approximately 100 nM and that this in vivo generated AS4.5 was indeed biologically active as an angiogenesis inhibitor. Most importantly, the administration of the Angiostatic Cocktail resulted in demonstrable anti-tumor activity in 4 of the first 5 patients treated. It is the purpose of this project, to further study the biochemical effects of the Angiostatic Cocktail for women with breast cancer. Studies will include development of assays for the AS4.5 monomer and complexes, as well as analysis of the biochemical and clinical responses of the Angiostatic Cocktail in the treatment of breast cancer.
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