MECHANISM OF ACTION OF DNA-REACTIVE ANTITUMOR DRUGS

点击翻译按钮获取中文摘要

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.