We propose a comprehensive program of research on the structure, affinities, kinetics and biological effects of drug-nucleic acid complexes. Drugs to be considered include actinomycins and anthracyclines, which are important clinical anticancer agents, as well as simpler intercalating compounds such as acridines and ethidium. Our objectives are to elucidate the structure and dynamics of drug-nucleic acid complexes, to determine base and sequence specificities and to assess strand breaking activity of these drugs in mammalian cells. By combining both in vitro and in vivo studies, we hope to understand the biological activity of the group of drugs in terms of molecular interactions. Techniques to be applied to these problems include 1H, 13C, 15N, 19F and 31 P NMR, absorption, fluorescence and stopped-flow kinetics in the case of physical chemical characterization of drug-nucleic acid complexes. Viscoelastometry will be used to assess drug effects on the conformation and integrity of chromosomal DNA from treated cells. The outcome of these studies should be an increase in our understanding of the mechanism of action of the drugs which eventually will lead to prediction of more effective drug structures. In addition, results from this research may also be important in terms of the mutagenic and possibly carcinogenic activities of these compounds.
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