MECHANISMS OF DRUG-INDUCED DNA DEGRADATION

药物引起的 DNA 降解机制

• 批准号: 3285487
• 负责人: John W Kozarich
• 金额: $ 21.66万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3285487
• 关键词: DNA; DNA replication; bleomycin; chemical reaction; chemical substitution; cobalt; conformation; copper; ethylenediaminetetraacetate; iron; manganese; metal complex; neoplasm /cancer chemotherapy; nucleic acid chemical synthesis; nucleic acid probes; nucleic acid sequence; nucleobase; nucleotide metabolism; phenanthrolines; polynucleotides; radiotracer; respiratory oxygen; ruthenium; tritium

This proposal seeks continued support for our studies directed toward the elucidation of the molecular mechanisms of DNA degradation by a variety of metal complexes, in particular the metallobleomycins (BLM). During the next funding period, we plan a comprehensive program which will include the following studies: 1. A complete analysis of the kinetic isotope effects on 4'- hydrogen abstraction by BLMs. We have designed methods to permit an accurate determination of these effects at individual sequence sites in a defined pBR322 fragment. This will allow us to study the potential effects of local conformation on the chemistry of the DNA-BLM interaction. 2. Continued investigations on the mechanism of deoxyribose ring fragmentation by Fe.BLM using 180 analysis. Our recent work has established that 180 incorporation into the phosphogycolate moiety is derived from the second 02 required for base propenal formation. Further studies are planned that will discriminate among several proposed pathways leading to cleavage. 3. The chemistry of BLM action on other DNA forms. Evidence suggests that BLM can react with A-form DNA. Model analysis has revealed that the chemistry of this process maydiffer from B DNA due to an altered accessibility of sugar hydrogens. Using techniques which we have developed, we will determine the mechanism of cleavage in appropriate model DNA's and DNA- RNA hybrids. Z DNA will also be studied. 4. The chemistry of other metallobleomycins. We plan to investigate the cleavage of DNA by cobalt-BLM and manganese- BLM. These complexes exhibit different activational requirements than the iron complex and yield different products. 5. The mode of BLM binding to DNA. The question of an intercalative vs. nonintercalative process for BLM binding remains open. Studies are planned to distinguish between these possibilities. 6. Model studies with other DNA cleaving agents. The probes which we have developed should be valuable in the determination of the mechanistic features of other agents which cleave DNA by hydrogen abstraction mechanisms. Ruthenium and cobalt complexes of 4,7-diphenylphenanthroline, methidium propyl- EDTA-Fe(II), and the 1,10-phenanthroline-copper complex are recent literature examples which are amenable to analysis by our technology.

这项建议旨在继续支持我们的研究， 致力于阐明DNA的分子机制 降解的各种金属络合物，特别是 金属球霉素（BLM）。 在下一个融资周期，我们 计划一个全面的计划，其中将包括以下内容 研究项目： 1. 对4 '- 通过BLM的氢提取。 我们设计了一些方法， 可以准确地确定这些影响，在个人 在一个确定的pBR 322片段的序列位点。 这将使我们能够 研究局部构象对化学性质的潜在影响 DNA与BLM的相互作用。 2. 脱氧核糖环作用机理的继续研究 使用180分析通过Fe.BLM进行碎片化。 我们最近的工作 确定180掺入磷酸乙醇酸 部分衍生自碱丙烯醛所需的第二个O2 阵 计划进行进一步的研究， 在几个提议的导致分裂的途径中。 3. BLM对其他DNA形式的化学作用。 证据 表明BLM可与A型DNA反应。 模型分析 揭示了这个过程的化学性质可能不同于B 由于糖氢的可及性改变而导致DNA。 使用 我们开发的技术，我们将确定 适当模型DNA和DNA中的切割机制- RNA杂交体。 Z DNA也将被研究。 4. 其他金属霉素的化学。 我们计划 研究了钴-BLM和锰-BLM对DNA的切割， BLM。 这些复合物表现出不同的激活作用 与铁络合物的要求不同，并产生不同的产品。 5. BLM与DNA的结合方式。 问题之 BLM结合的嵌入与非嵌入过程 仍然开放。 计划进行研究以区分这些 可能性 6. 与其他DNA裂解剂的模型研究。 探针 我们所开发的技术应该是有价值的， 其他通过切割DNA的试剂的机械特征， 氢提取机制 钌和钴 4，7-二苯基菲咯啉、丙基甲脒 EDTA-Fe（II）和1，10-菲咯啉-铜络合物， 最近的文献例子，这是经得起分析，我们的 技术.