MECHANISM OF ACTION OF DNA-REACTIVE ANTITUMOR DRUGS

长期目标是在分子水平上阐明 DNA链断裂剂治疗效果的基础， 单独使用或组合使用。 首先，我们想澄清一下 这些类型的药物是否具有细胞毒性，因为1） 对基因组的随机损伤的累积或2）对 基因组的特定区域。 识别新的和/或 将评估药物作用的具体部位， 与药物诱导的细胞毒性的关系。 具体目标是： 1. 评估DNA复杂性增加的影响 环境和药物切割DNA的能力。 Insights about DNA的结构和环境对DNA损伤的影响 药物或药物组合的潜力及其修复将是 寻找。 该分析提供了链断裂的定量数据 药物诱导单链和/或双链裂解的能力 在日益复杂的环境中转化为DNA（无细胞DNA， 小鼠研究）。 2. 确定药物作用于基因组DNA的优先位点。 本项目将评估DNA链的优先相互作用 基因组DNA中的断裂剂。 目标是寻找 表明药物选择性地攻击基因组DNA， 是否存在特定位点的DNA损伤。 此外，本发明还提供了一种方法， 不同亚群基因组的优先损伤和修复 评价DNA（转录和复制染色质）。 3. 评估细胞毒性潜力与 和药物对基因组DNA的损伤 三项具体研究是 提议： 研究1. 识别具有独特能力的药物 与基因组DNA相互作用。 研究2. 确定哪些类型的药物与基因组相互作用 DNA可以预测细胞毒能力。 研究3. 评价设计用于调节特定 药物对基因组的影响， 细胞毒 最后，单独或联合使用药物进行评价， 通过监测改善荷瘤小鼠的治疗益处 药物对肿瘤转化附加体元件的作用。

The long-term objective is to elucidate at the molecular level the basis of therapeutic efficacy of DNA strand scission agents when used alone or in combination. Initially, we would like to clarify whether these type of drugs are cytotoxic because of 1) an accumulation of random damage to the genome or 2) damage to specific regions of the genome. The identification of novel and/or specific sites of drug action will be assessed for their relationship to drug-induced cytotoxicity. The specific aims are: 1. Evaluate the influence of increasing complexity of the DNA environment and the ability of drugs to cleave DNA. Insights about how the structure and environment of DNA influence the DNA damaging potential and its repair of drugs or drug combinations are to be sought. The assays provide quantitative data on a strand scissions drug's ability to induce single and/or double stranded cleavages into DNA in increasingly complex environments (cell-free DNA to mouse studies). 2. Determine preferential sites of drug action on genomic DNA. This project will evaluate preferential interaction of DNA strand scission agents within genomic DNA. The objective is to search for indications that drugs selectively attack genomic DNA, that is whether there is site specific DNA damage. In addition, preferential damage and repair of various subpopulations of genomic DNA (transcribing and replicating chromatin) is evaluated. 3. Assess the possible relationships between cytotoxic potential and drug damage to genomic DNA. Three specific studies are proposed: Study 1. Identification of drugs which possess unique abilities to interact with genomic DNA. Study 2. Ascertain which types of drug interactions with genomic DNA can predict cytotoxic capability. Study 3. Evaluate drug combinations designed to modulate specific drug effects on the genome with a corresponding change in cytotoxicity. Finally, drugs alone or in combinations are to be evaluated for improved therapeutic benefit in tumor-bearing mice by monitoring drug action on a neoplastically transforming episomal element.