MOLECULAR PHARMACOLOGY OF TUMOR AND VIRUS INHIBITORS

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This research investigates the relationship of DNA damage to processes involved in chemical mutagenesis. nucleoside adducts, derived from chemical carcinogens, chemotherapeutic agents and products of ionizing radiation, will be incorporated, site-specifically, into synthetic oligodeoxynucleotides. The mutagenic spectra of these lesions will be determined in mammalian cells and bacteria. New protecting groups will be developed that will permit site-specific incorporation of alkali-sensitive adducts into oligodeoxynucleotides. Synthetic methods for introducing crosslinks and pre-selected positions in duplex DNA will be established. Chemically-modified oligodeoxynucleotides will be used to explore molecular mechanisms by which DNA polymerases copy damaged templates and to delineate the process of DNA replication and repair, with special reference to chemical mutagenesis. Experimental systems will be developed which allow chemically-modified DNA to be integrated into chromosomal DNA and subsequently rescue for mutational analysis. Damaged DNA will be examined for its ability to enhance homologous recombination. The precise relationship between the number and location of DNA lesions and the induction of the SOS response will be determined. Physical methods, including 2D-NMR and molecular model building, will be used to establish the three dimensional structure of chemically-modified oligodeoxynucleotides in solution. The mutagenicity of the radiomimetic agent, bleomycin, could arise from the abasic sites, 3-phosphoglycolate residues, and/or nucleoside base propenals produced when this antibiotic reacts with DNA. We will examine the mutagenicity of the two structural lesions and characterize the adducts formed when nucleoside base propenals react with DNA. The significance of this research lies in establishing a molecular basis for the mutagenic effects of various types of DNA damage and in demonstrating its relationship to DNA repair. These phenomena are fundamental to an understanding of the primary events involved in chemical carcinogenesis.