DNA LIGASE I AS A POTENTIAL TARGET FOR ANTICANCER DRUGS

描述：本申请的总体目标是探索 人类DNA连接酶I可能是一个潜在的靶点， 通过研究DNA连接酶I与抗癌治疗的关系， 表达和肿瘤过程。 人类DNA连接酶I是一种必需的 在DNA复制、转录、修复和 通过将单链和双链DNA与形成的 磷酸二酯键。 有令人信服的证据表明人类DNA连接酶 I在快速增殖的细胞如肿瘤细胞中更活跃。 这表明DNA连接酶I可能是一种非常有趣和独特的 抗癌剂靶向，且有很大可能性， 通过使用，实现针对快速增殖的肿瘤细胞的选择性， DNA连接酶I相互作用剂。 申请人建议测试 假设人DNA连接酶I的表达与细胞凋亡密切相关， 肿瘤过程，并针对人类DNA连接酶I提供了一个潜在的 增强的治疗益处。 建议的具体目标如下：1） 评估人类肿瘤与正常组织中的人类DNA连接酶I水平。 （二） 探讨人DNA连接酶I基因表达的调控机制。 3)测试DNA连接酶I抑制是否产生抗肿瘤活性 临床前体外和体内评价系统中的反义策略。 4)开发灵敏且可重复的DNA连接酶I检测方法。

DESCRIPTION: The overall object of this application is to explore the possibility that human DNA ligase I could be a potential target in anticancer therapy by investigating the relationship between DNA ligase I expression and the neoplastic process. Human DNA ligase I is an essential enzyme required during DNA replication, transcription, repair, and recombination by joining single- and double-stranded DNA with the formation of phosphodiester bonds. There is compelling evidence that human DNA ligase I is much more active in rapidly proliferating cells such as tumor cells. This suggests that DNA ligase I could be a very interesting and unique target for anticancer agents and that there is a very strong possibility for achieving the selectivity against rapidly proliferating tumor cells by using DNA ligase I-interactive agents. The applicant proposes to test the hypothesis that human DNA ligase I expression is tightly related to the neoplastic process, and targeting human DNA ligase I offers a potential for enhanced therapeutic benefit. The following specific aims are proposed: 1) Assess human DNA ligase I levels in human tumors versus normal tissue. 2) Investigate the regulatory mechanisms of human DNA ligase I gene expression. 3) Test whether DNA ligase I inhibition produces antitumor activity using antisense strategy in preclinical in vitro and in vivo evaluation systems. 4) Develop a sensitive and reproducible assay for DNA ligase I.