Antiangiogenic therapy of cancer has now been demonstrated in tumor-bearing animals and awaits clinical trial. We envision that antiangiogenic therapy may be eventually employed as: adjuvant therapy; as prophylactic therapy to prevent tumor recurrence; or as antimetastatic therapy. As new angiogenesis inhibitors are discovered therapeutic indications may widen. Antiangiogenic therapy may be directed against two mechanisms of tumor angiogenesis. One mechanism involves the switch to the angiogenic phenotype in tumor cells. Extracellular secretion of an otherwise cell- associated angiogenic molecule such as bFGF, is one example of this switch. A second mechanism involves the target of these angiogenic molecules, the vascular endothelium. Studies of this mechanism have led to an effort to block vascular endothelium from being stimulated by any angiogenic molecule. A potent fungal derived, relatively non-toxic angiogenesis inhibitor (of the """"""""anti-endothelial"""""""" type) has been discovered in our laboratory and a synthetic analogue has been made for us. In this project we propose: (i) to study specific properties of this inhibitor in preparation for clinical trial; and (ii) to carry out additional experiments which will advance our understanding of anti- endothelial angiogenesis inhibition in general. These studies are designed to address the following questions: (1) Does drug resistance develop against angiogenesis inhibitors? (2) Can angiogenic activity be detected in patients with cancer? (3) Can a quantitative bioassay be developed for antiangiogenic activity? (4) Is the mechanism of growth arrest in ectopic spleens which develop from intraperitoneal implantation of spleen cells (splenosis), dependent upon endogenous angiogenesis inhibitors?
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