DNA TOPOISOMERASE I TARGET INTERACTIONS OF CAMPTOTHECINS

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DESCRIPTION (Applicant's Description): The research objective of this five- year grant application is to explore the molecular level details of the DNA and topoisornerase I interactions of the camptothecin family of anticancer drugs. The research will take place at University of Kentucky, Department of Chemistry and College of Pharmacy. Camptothecin is an experimental anticancer agent renowned for its novel mechanism of action, the inhibition of DNA- processing enzyme topoisomerase I. Two camptothecins (TPT and CPT-11) have recently gained the U.S. Food and Drug Administration's approval for clinical use in 1996 and 1998. The project involves the implementation of a variety of state-of-the-art analytical and biophysical methods including high field nuclear magnetic resonance spectroscopy (NMR), computer molecular modeling, high pressure liquid chromatography, high sensitivity differential scanning c a l o rimetry and isothermal titration calorimetry, photon correlation spectroscopy, laser-induced one- and two-photon fluorescence spectroscopy, and Fourier transform mass spectrometry. This variety of highly complementary biophysical methods provides a powerful approach for obtaining a detailed, biophysical view of the target interactions of the camptothecins. The aim of the project is to understand the molecular level details of the interactions of clinically relevant water-soluble as well as lipophilic camptothecins with dsDNA and genomic DNA. Molecular level details of cleavable complexes formed between dsDNA, topoisomerase I and camptothecin drugs will be sought. Also to be studied is the structural basis of drug binding in dsDNA and cleavable c o m plexes. Mechanistic information and structure-function correlations concerning the inhibition of topoisomerase I function by camptothecins will be pursued. This research project is intended to define the academic research program of Dr. Yang who is intent on achieving a faculty position in a first- rate research-oriented College of Pharmacy or Medicine in the United States.