ANTIANGIOGENESIS BY THYMIDINE PHOSPHORYLASE INHIBITORS

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DESCRIPTION (Adapted from the application): The growth and metastasis of solid tumors are angiogenesis-dependent. One angiogenesis factor, platelet-derived endothelial cell growth factor (PD-ECGF), is identical with thymidine phosphorylase (TP), an enzyme of thymidine metabolism and homeostasis. This program is designed to establish a convenient model to study the role of human, recombinant PDECGF/TP in angiogenesis in vivo, and to synthesize potent inhibitors of the enzyme that can be evaluated for antiangiogenic activity as potential antitumor drugs for human use. The specific aims of phase I of this project are: (1) To synthesize more potent analogs of a lead inhibitor of PD-ECGF/TP, and assay them for inhibition of recombinant, baculovirus-expressed PD-ECGF/TP. (2) To establish the mouse cornea micropocket assay as a means of testing the angiogenic activity of recombinant PD-ECGF/TP in vivo. (3) To test the ability of a potent inhibitor of PD-ECGF/TP to block angiogenesis in the mouse corneal micropocket assay following topical administration. (4) To synthesize hydrophilic and/or salt-forming, water soluble derivatives of the best lead compound from aim 3, and to measure their potency as inhibitors of PD-ECGF/TP. In Phase II of this project we will extend the in vivo studies to evaluate the antitumor activity of systemically administered drugs, determine dose-response relationships for the drug(s), and obtain acute and chronic toxicity profiles of a lead drug candidate. We will seek a partnership with a pharmaceutical company to assist in further development of a lead drug toward preclinical study. PROPOSED COMMERCIAL APPLICATION: Treatment or adjunct to treatment of angiogenesis dependent human cancer.