MECHANISM OF ACTION OF DNA-REACTIVE ANTITUMOR DRUGS

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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.