MOLECULAR MECHANISM OF ACTION OF ANTITUMOR ALKYLATING AGENTS

抗肿瘤烷基化剂的分子作用机制

• 批准号: 3838033
• 负责人: P M O'CONNOR
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838033
• 关键词: DNA; DNA damage; DNA repair; DNA replication; alkylating agents; antineoplastics; cell cycle proteins; cell type; drug design /synthesis /production; drug metabolism; enzyme mechanism; lymphoma; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nitrogen mustard; phosphorylation; protein kinase; tissue /cell culture; xanthine analog

This project now focusses primarily on cell cycle regulation as a major determinant of cytotoxic responses to alkylating agents and other DNA damaging anticancer drugs. We are utilizing recently developed tools and concepts to investigate the relationships between cell cycle regulation and the ability of cells to survive DNA damage. Our current studies focus on the mechanisms by which recognition of DNA damage is signalled to the molecular checkpoints that govern cell cycle progression from G2 phase into mitosis, and from G1 into S phase. Our long-range objective is apply new knowledge on cell cycle control to future anticancer drug development and therapy. In studies of the G2 checkpoint, we found that G2 arrest in nitrogen mustard treated human lymphoma cells was not due to lack of cdc2 or cyclin B; components of the critical kinase complex that controls cell cycle progression through this checkpoint. Rather, cdc2 kinase activation remains suppressed due to persistence of inhibitory phosphorylations. We are now investigating the mechanism which determines inhibitory phosphorylations, and hope to trace the sequence of events back to the point where DNA damage is recognized. In future studies, special attention will be given to differences among cell types that may explain why some cancer cells are selectively sensitive to DNA damaging drugs. We are also studying the cdk2-cyclin A kinase complex, whose exact role in the cell cycle is still uncertain; we found that, contrary to the cdc2-cyclin B kinase complex, its activity continued to rise in G2-arrested cells. In addition, we are studying the mechanisms by which drugs such as methylxanthines are able to circumvent DNA damage-induced G2 arrest. Compounds that influence cell cycle control may prove useful modulators of DNA damaging chemotherapies.

这个项目现在主要集中在细胞周期调控作为一个主要的 对烷化剂和其它DNA的细胞毒性反应的决定因素 破坏抗癌药物。 我们正在利用最近开发的工具， 研究细胞周期调控与 以及细胞在DNA损伤后存活的能力。 我们目前的研究 重点是识别DNA损伤的信号机制 到控制细胞周期从G2期进展的分子关卡 从G1期进入S期。 我们的长远目标 将细胞周期控制新知识应用于未来的抗癌药物 发展和治疗。 在对G2检查点的研究中，我们发现， 在氮芥处理的人淋巴瘤细胞中G2阻滞不是由于 缺乏cdc 2或细胞周期蛋白B;关键激酶复合物的组分， 通过这个检查点控制细胞周期进程。 相反，CDC 2 由于抑制性激酶的持续存在，激酶活化仍然受到抑制。 磷酸化 我们现在正在研究 确定抑制磷酸化，并希望跟踪序列 事件回到DNA损伤被识别的点。 今后 研究中，将特别注意细胞类型之间的差异 这可能解释了为什么一些癌细胞对DNA选择性敏感， 有害药物 我们也在研究cdk 2-细胞周期蛋白A激酶复合物， 其在细胞周期中的确切作用仍然不确定;我们发现， 与cdc 2-细胞周期蛋白B激酶复合物相反，其活性持续， G2停滞细胞增加。 此外，我们还在研究 甲基黄嘌呤等药物能够绕过DNA G2期阻滞。 影响细胞周期控制的化合物 可能证明是DNA损伤化疗的有用调节剂。