DNA LIGASE I AS A POTENTIAL TARGET FOR ANTICANCER DRUGS

描述：此应用程序的总体目标是探索 人类DNA连接酶I可能成为 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是一种必不可少的 DNA复制、转录、修复和修复所需的酶 通过连接单链和双链DNA与形成的重组 磷酸二酯键。有令人信服的证据表明人类DNA连接酶 在快速增殖的细胞中，如肿瘤细胞，I要活跃得多。 这表明DNA连接酶I可能是一种非常有趣和独特的 作为抗癌药物的靶标，有很大的可能性 实现对快速增殖的肿瘤细胞的选择性 DNA连接酶I-相互作用试剂。申请者提议测试 假设人类DNA连接酶I的表达与 肿瘤过程和靶向人类DNA连接酶I提供了一种潜在的 提高了治疗效益。提出了以下具体目标：1) 评估人类肿瘤组织和正常组织中的人类DNA连接酶I水平。2) 探讨人DNA连接酶I基因表达的调控机制。 3)检测DNA连接酶I抑制是否产生抗肿瘤活性 反义策略在临床前体外和体内评价系统中的应用。 4)建立了一种灵敏、重复性好的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.