Chemotherapy is an important tool in the clinical management of cancer. The long-term objective of the research proposed here is to elucidate the structure and dynamics of anticancer drug-DNA complexes in order to enhance our understanding of their mechanism of action and our ability to design new, more effective drugs. In order to achieve this objective, we propose to apply a variety of spectroscopic techniques to the analysis of drug-DNA interactions. The principal tool proposed for structural investigation is high resolution proton NMR in one and two dimensions. We plan to study the oligonucleotide complexes of several different antitumor antibiotics, including chromomycin and its analogs mithramycin and olivomycin, along with actinomycin and nogalomycin. We will be investigating the structure and sequence specificity of these drug-DNA complexes using one dimensional experiments and two dimensional COSY, HOHAHA and NOESY experiments. Results will be analyzed by a combination of computer graphics, complete relaxation matrix analysis, energy minimization, and distance geometry. In addition to standard DNA duplexes, we will examine the effects of DNA modification, such as methylation, on the structure of these complexes. Finally, the proposed structural studies based on NMR methods will be complemented by equilibrium and kinetic binding studies to provide a thermodynamic framework for their interpretation.
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