ANTIANGIOGENESIS BY THYMIDINE PHOSPHORYLASE INHIBITORS

描述(改编自应用程序)：生长和转移 的实体瘤是依赖血管生成的。一种血管生成因子， 血小板衍生的内皮细胞生长因子(PD-ECGF)，是相同的 与胸苷代谢酶胸苷磷酸化酶(TP)和 动态平衡。本程序旨在建立一个方便的模型 研究人重组PDECGF/TP在血管生成中的作用 体内，并合成有效的酶抑制剂，可以 作为潜在的抗肿瘤药物的抗血管生成活性评价 为人类所用。 本项目第一阶段的具体目标是：(1)合成更多 一种有效的PD-ECGF/TP的铅抑制剂类似物，并测定它们的 抑制重组杆状病毒表达的PD-ECGF/TP。(2)至 建立小鼠角膜微袋试验作为检测小鼠角膜微囊的方法 重组PD-ECGF/TP体内血管生成活性的研究(3)测试 一种有效的PD-ECGF/TP抑制剂阻断血管生成的能力 局部给药后的小鼠角膜微袋分析。(4) 合成亲水性和/或成盐性的水溶性衍生物 来自目标3的最好的先导化合物，并测量它们的效力 PD-ECGF/TP的抑制剂。 在这个项目的第二阶段，我们将把体内研究扩展到 评估全身用药的抗肿瘤活性， 确定药物(S)的剂量-反应关系，并获得急性 以及一种候选先导药物的慢性毒性。我们将寻求一种 与一家制药公司合作，协助进一步 用于临床前研究的先导药物的开发。 建议的商业应用： 血管生成依赖型人的治疗或辅助治疗 癌症。

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.