Abstract

The long term goals of this research are characterization of the nature of DNA relaxation by eukaryotic DNA topoisomerase I at a molecular level and identification of those parameters of topoisomerase I inhibition that are critical for the expression of anti-tumor activity. This should permit the identical of second generation topoisomerase I inhibitors suitable for development as anti-tumor agents. For the period of requested support, the specific aims include better definition of the nature of inhibitor binding by the topoisomerase I-DNA covalent binary complex, the identification of an optimal system for studying topoisomerase I-DNA interaction at high resolution and exploration of the possible role of other cellular factors in the expression of cytotoxicity by topoisomerase I inhibitors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078415-04
Application #
6624676
Study Section
Special Emphasis Panel (ZRG1-BNP (03))
Program Officer
Fu, Yali
Project Start
1999-12-23
Project End
2003-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
4
Fiscal Year
2003
Total Cost
$195,007
Indirect Cost

  Institution

Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Arimondo, Paola B; Thomas, Craig J; Oussedik, Kahina et al. (2006) Exploring the cellular activity of camptothecin-triple-helix-forming oligonucleotide conjugates. Mol Cell Biol 26:324-33
Gao, Rong; Zhang, Yi; Dedkova, Larisa et al. (2006) Effects of modification of the active site tyrosine of human DNA topoisomerase I. Biochemistry 45:8402-10
Cheng, Kejun; Rahier, Nicolas J; Eisenhauer, Brian M et al. (2005) 14-azacamptothecin: a potent water-soluble topoisomerase I poison. J Am Chem Soc 127:838-9
Arimondo, Paola B; Laco, Gary S; Thomas, Craig J et al. (2005) Activation of camptothecin derivatives by conjugation to triple helix-forming oligonucleotides. Biochemistry 44:4171-80
Hecht, Sidney M (2005) Camptothecin: roles of the D and E rings in binding to the topoisomerase I-DNA covalent binary complex. Curr Med Chem Anticancer Agents 5:353-62
Gao, Rong; Zhang, Yi; Choudhury, Ambar K et al. (2005) Analogues of vaccinia virus DNA topoisomerase I modified at the active site tyrosine. J Am Chem Soc 127:3321-31
Rahier, Nicolas J; Eisenhauer, Brian M; Gao, Rong et al. (2005) On the role of E-ring oxygen atoms in the binding of camptothecin to the topoisomerase I-DNA covalent binary complex. Bioorg Med Chem 13:1381-6
Tian, Ligeng; Claeboe, Christopher D; Hecht, Sidney M et al. (2005) Mechanistic plasticity of DNA topoisomerase IB: phosphate electrostatics dictate the need for a catalytic arginine. Structure 13:513-20
Rahier, Nicolas J; Cheng, Kejun; Gao, Rong et al. (2005) Synthesis of 14-azacamptothecin, a water-soluble topoisomerase I poison. Org Lett 7:835-7
Rahier, Nicolas J; Eisenhauer, Brian M; Gao, Rong et al. (2004) Water-soluble camptothecin derivatives that are intrinsic topoisomerase I poisons. Org Lett 6:321-4

Showing the most recent 10 out of 20 publications