MECHANISM OF ACTION OF DNA-REACTIVE ANTITUMOR DRUGS

这个项目将研究链效应之间的关系 对DNA结构和细胞毒性的断裂抗肿瘤剂/治疗 有效性 有四个主要目标。 (i)开发一个模型系统， 选择DNA反应性药物的组合， 增强了链断裂药物的潜力。 药物是细胞性的 靶核小体DNA将被第二种抗肿瘤药物干扰， 可以解开DNA结构。 药物作用的变化 核小体DNA，包括核酸内切酶消化率和 将沿着药物细胞毒性的变化来确定作用。 （二） 分析额外的DNA链断裂药物对 核小体DNA 新的断链药物将被测试，以确定 它们与核小体DNA相互作用的能力。 这将扩大范围 可以在目标1所述的药物组合中进行测试的药物。 (iii)分析DNA断链药物对核小体DNA的影响 in vivo. 这些研究将扩展我们的体外观察，以表明， 这些试剂在体内以类似的方式起作用。 的组合药物 分析将最终将药物对核小体DNA的作用与 治疗效果的变化。 (iv)分析DNA链断裂 药物与活跃转录基因和复制的相互作用 染色质 这项工作将扩大切割药物对核小体DNA的作用 这些物质如何切割转录基因和复制染色质。 DNA干扰药物将被用来改变切割药物对细胞的作用。 核小体DNA的独特区域。 药物作用的变化将是 与体外细胞毒性和治疗性 在体内的有效性。

This project will examine the relationship between the effects of strand scission antitumor agents on DNA structure and cytotoxicity/therapeutic effectiveness. There are 4 main aims. (i) Develop a model system designed to select combinations of DNA reactive drugs in which the therapeutic potential of a strand scission drug is enhanced. The drug's cellular target, nucleosomal DNA, will be perturbed by a second antitumor drug that can unwind DNA structure. The change in scission drug action on nucleosomal DNA, including rate of endonucleolytic digestion and site of action will be determined along with changes in drug cytotoxicity. (ii) Analyze additional DNA strand scission drugs for their effects on nucleosomal DNA. New strand scission drugs will be tested to determine their ability to interact with nucleosomal DNA. This will extend the range of drugs that can be tested in the drug combinations described in aim 1. (iii) Analyze the effects of DNA strand scission drugs on nucleosomal DNA in vivo. These studies will extend our in vitro observations to show that these agents behave in a similar fashion in vivo. The combination drug analysis will culminate in relating drug action on nucleosomal DNA to changes in therapeutic effectiveness. (iv) Analyze DNA strand scission drug interaction with actively transcribing genes and replicating chromatin. This work will extend scission drug effects on nucleosoma DNA to how these agents cleave transcribing genes and replicating chromatin. DNA perturbing drugs will be used to modify scission drug action on the unique regions of nucleosomal DNA. Changes in drug action will be correlated with changes in cytotoxicity in vitro and therapeutic effectiveness in vivo.