Abstract

): 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA083886-06
Application #
6753601
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2000-04-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
6
Fiscal Year
2004
Total Cost
$148,888
Indirect Cost

  Institution

Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721

  Publications

Lin, Clement; Yang, Danzhou (2015) DNA Recognition by a Novel Bis-Intercalator, Potent Anticancer Drug XR5944. Curr Top Med Chem 15:1385-97
Lin, Clement; Mathad, Raveendra I; Zhang, Zhenjiang et al. (2014) Solution structure of a 2:1 complex of anticancer drug XR5944 with TFF1 estrogen response element: insights into DNA recognition by a bis-intercalator. Nucleic Acids Res 42:6012-24
Punchihewa, Chandanamali; Carver, Megan; Yang, Danzhou (2009) DNA sequence selectivity of human topoisomerase I-mediated DNA cleavage induced by camptothecin. Protein Sci 18:1326-31
Ambrus, Attila; Yang, Danzhou (2007) Diffusion-ordered nuclear magnetic resonance spectroscopy for analysis of DNA secondary structural elements. Anal Biochem 367:56-67
Punchihewa, Chandanamali; Dai, Jixun; Carver, Megan et al. (2007) Human topoisomerase I C-terminal domain fragment containing the active site tyrosine is a molten globule: implication for the formation of competent productive complex. J Struct Biol 159:111-21
Dai, Jixun; Carver, Megan; Punchihewa, Chandanamali et al. (2007) Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: insights into structure polymorphism of the human telomeric sequence. Nucleic Acids Res 35:4927-40
Dai, Jixun; Punchihewa, Chandanamali; Ambrus, Attila et al. (2007) Structure of the intramolecular human telomeric G-quadruplex in potassium solution: a novel adenine triple formation. Nucleic Acids Res 35:2440-50
Dai, Jixun; Chen, Ding; Jones, Roger A et al. (2006) NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region. Nucleic Acids Res 34:5133-44
Dai, Jixun; Dexheimer, Thomas S; Chen, Ding et al. (2006) An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. J Am Chem Soc 128:1096-8
Ambrus, Attila; Chen, Ding; Dai, Jixun et al. (2006) Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution. Nucleic Acids Res 34:2723-35

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