ANTIANGIOGENESIS BY THYMIDINE PHOSPHORYLASE INHIBITORS

描述（改编自应用程序）：生长和转移 实体瘤的生长依赖于血管生成。一种血管生成因子， 血小板衍生内皮细胞生长因子（PD-ECGF）， 胸苷磷酸化酶（TP），一种胸苷代谢酶， 体内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， 评价了作为潜在抗肿瘤药物的抗血管生成活性， 人类使用。 该项目第一阶段的具体目标是：（1）综合更多的 PD-ECGF/TP的先导抑制剂的有效类似物，并测定它们的 抑制重组杆状病毒表达的PD-ECGF/TP。(2)到 建立小鼠角膜微囊试验作为测试方法 重组PD-ECGF/TP在体内的血管生成活性。(3)测试 PD-ECGF/TP的有效抑制剂阻断血管生成的能力 局部给药后的小鼠角膜微囊测定。（四） 合成亲水和/或成盐的水溶性衍生物 目标3中最好的先导化合物，并测量其效力， PD-ECGF/TP的抑制剂。 在该项目的第二阶段，我们将扩展体内研究， 评价全身给药药物的抗肿瘤活性， 确定药物的剂量-反应关系，并获得急性 和慢性毒性特征。我们将寻求一个 与一家制药公司建立伙伴关系， 临床前研究的先导药物的开发。 拟定商业应用： 血管生成依赖性人的治疗或辅助治疗 癌

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.