INHIBITION OF DNA REPLICATION BY DNA DAMAGING DRUGS

DNA 损伤药物对 DNA 复制的抑制

• 批准号: 6150248
• 负责人: TERRY A BEERMAN
• 金额: $ 28.82万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150248
• 关键词: DNA damage; DNA replication; antimetabolites; cell cycle; drug design /synthesis /production; pharmacokinetics; virus DNA

DESCRIPTION: Many different types of DNA-damaging drugs are used as chemotherapeutic agents. The DNA damage caused by these drugs leads to therapeutic effects through as yet incompletely characterized mechanism(s) although inhibition of DNA replication is widely recognized as a potential mechanism. Our goal is to develop paradigms for inhibition of DNA replication caused by DNA-damaging anticancer drugs. The approach utilizes well-defined intracellular Simian Virus 40 and Epstein-Barr Virus DNA to determine whether inhibition of DNA replication by a limited number of DNA-damaging agents with specific and well-characterized mechanisms of action occurs at the level of initiation, elongation or both and whether inhibition occurs via cis or trans mechanisms. Identification of cellular proteins contributing to the inhibition of DNA replication, possibly including those involved in cell cycle checkpoints, will be sought. The specific aims are as follows: Aim 1. Characterize DNA-damaging drugs for their ability to inhibit DNA replication a the level of initiation, elongation or both. Aim 2. Characterize DNA-damaging drugs for their ability to inhibit DNA replication in cis or trans. Aim 3. Characterize mechanism(s) by which trans-acting DNA-damaging agents inhibit replication.

描述：许多不同类型的DNA破坏药物被用作 化学治疗剂。 这些药物造成的DNA损伤导致 通过尚未完全表征机制的治疗作用 尽管抑制DNA复制被广泛认为是电位 机制。 我们的目标是开发抑制DNA的范例 由DNA损害抗癌药引起的复制。 该方法利用 定义明确的细胞内邻肌病毒40和爱泼斯坦 - 巴尔病毒DNA至 确定是否通过有限数量的抑制DNA复制 具有特定且特征良好的机制的DNA损害剂 行动发生在启动，伸长率或两者兼而有之 通过顺式或反式机制发生抑制作用。 鉴定细胞 有助于抑制DNA复制的蛋白质，可能 包括参与细胞周期检查点的那些，将寻求。 这 具体目的如下：目标1。表征DNA受损药物 它们抑制DNA复制的能力A的启动水平， 伸长或两者兼而有之。 AIM 2。为其特征DNA损害药物的特征 能够抑制顺式或反式的DNA复制的能力。 AIM 3。表征跨作用DNA损害剂的机制 抑制复制。