Tumor progression is angiogenesis dependent. Numerous antiangiogenic molecules have been described including fragments of endogenous proteins as well as small molecule inhibitors blocking proangiogenic signaling. These are in clinical development so that there is no currently approved FDA drug that is specifically antiangiogenic. We have """"""""searched"""""""" for FDA approved compounds that may have antiangiogenic side effects, utilizing hints from the clinical and scientific literature, as well as suggestions on how to generate antiangiogenic protein fragments in vivo, thereby obviating the need to administer them. Our preliminary studies show that a cocktail of tissue plasminogen activator (tPA) and captopril generates potent in vitro and in vivo antiangiogenic effects, the latter in mice and in a patient with cancer. Moreover, the biological effects seen cannot be explained by the generation of angiostatin, a fragment of plasminogen, the original raison d'etre for this cocktail as proposed by Soft et al. During the course of these studies, we have discovered that thrombin has antiangiogenic activity. Laboratory and clinical extension of these findings constitutes the aims of this application. ? Aim 1: To test the anti-tumor efficacy of plasminogen activators and captopril in animal models ? Aim 2: To assess whether antiangiogenic activity can be safely generated in the blood of patients with ? advanced malignancies by administration of tPA and captopril ? Aim 3: To probe the molecular pathways by which thrombin exerts its antiangiogenic effect ? Aim 4: To purify the active antiangiogenic moiety from the blood of patients treated with tPA and captopril. These studies will set the stage for a Phase II trial of the tPA and captopril regimen for cancer therapy and perhaps for treating other angiogenesis dependent diseases as well. ? ?
