MOLECULAR BIOLOGY OF CAMPTOTHECIN INDUCED DNA DAMAGE

喜树碱引起的 DNA 损伤的分子生物学

• 批准号: 6377080
• 负责人: ROBERT M SNAPKA
• 金额: $ 19.85万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-08 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377080
• 关键词: DNA damage; DNA replication; DNA topoisomerases; RNA splicing; ataxia telangiectasia; camptothecin; deafness; dwarfism; enzyme activity; enzyme inhibitors; genetic transcription; molecular biology; phosphoester ligase; retina degeneration; simian virus 40; tissue /cell culture; virus DNA

Camptothecins are a very promising group of strong topoisomerase I poisons that have shown good activity against a variety of human cancers in clinical trials. Several key contributions to our understanding of the cytotoxic mechanisms of camptothecins have been made with studies of simian virus 40 (SV40), a small double strand DNA virus which makes such extensive use of host cell chromosomal proteins and enzymes of DNA replication and transcription that it is considered a "minichromosome" and model for the mammalian replicon. As a model system, SV40 has unique advantages and has made many contributions to our understanding of mammalian DNA replication and transcription. The hypothesis of this proposed study is that our understanding of the molecular biology of camptothecin action can be significantly advanced by two developments of the SV40 model system: (1) the study of camptothecin-resistant mutants of CV-1 host cells for SV40 infections and (2) studies using mutants of SV40 with greatly increased infectivity for human cells. The primary goal of the studies is to understand the structure and processing of camptothecin-induced DNA lesions and how these can be modulated by other treatments. The unique advantages of the SV40 system will allow us to analyze disruptions in DNA replication and transcription in unusual molecular detail. Secondary goals include complete characterization of the camptothecin resistant CV-1 cell mutants, studies of camptothecin effects on DNA replication in human genetic instability syndromes hypersensitive to camptothecins and understanding of the roles of topoisomerases I and IIbeta in transcription. The rational for the studies is that improved understanding of camptothecin-induced damage and its processing will provide valuable information for the design of new drugs of this class and for new treatment combinations.

Camptothecins是一组非常有前途的强拓制蛋白酶I毒药，在临床试验中对各种人类癌症表现出良好的活性。 对我们对甲虫病毒40（SV40）的研究已经做出了对我们对凸轮皮蛋白的细胞毒性机制的理解的一些关键贡献，这是一种小的双链DNA病毒，它如此广泛地使用了宿主细胞染色体蛋白和DNA复制和转录酶，以至于被认为是“ Minichromosome”和“ Minichromosome”模型的DNA复制和转录。 作为模型系统，SV40具有独特的优势，并为我们对哺乳动物DNA复制和转录的理解做出了许多贡献。 这项提出的研究的假设是，我们对Camptothecin作用的分子生物学的理解可以通过SV40模型系统的两个发展显着提高：（1）研究SV40感染的CV-1抗宿主细胞的CV-1耐药性突变体的研究，以及（2）使用具有大大增加Infectivity SV40的突变体的研究。 研究的主要目的是了解甲虫诱导的DNA病变的结构和处理，以及其他治疗方法如何调节这些病变。 SV40系统的独特优势将使我们能够以异常的分子细节分析DNA复制和转录的破坏。 次要目标包括抗甲虫耐药的CV-1细胞突变体的完全表征，对人遗传不稳定性综合征对Camptothecins敏感的DNA复制的研究以及对topoisomerase I和IIBETA转录中的作用的理解。 研究的理性是，对山普斯汀诱导的损害的了解得以提高，将为设计该类别的新药物和新的治疗组合提供宝贵的信息。