Abstract

The overall aim is to develop deoxynucleoside analogs for the treatment of patients with cancer. This includes the study of the mechanisms of action and resistance as well as the exploration of novel strategies to develop new nucleoside analogs with unique properties. In this application, we will focus on the study of the antitumor action of a novel L-nucleoside analog, L(-)dioxolane cytidine (L(-)OddC) discovered in this laboratory. This is based on the study section's recommendation.
The Specific Aims are listed: A. Study the effect of nucleoside transport inhibitors on the uptake of L(-)OddC B. Study the intracellular metabolism of L(-)OddC C. Examine the interaction of L(-)OddC and its metabolites with relevant human enzymes D. Examine the antitumor activity of L(-)OddC against human tumor in nude mouse models In addition, we will continue to collaborate with and to serve as a resource to medicinal chemistry laboratories which share common related interests. This proposed study should provide information not only in terms of new drug discovery, but also some basic knowledge regarding the biochemical pharmacology of deoxynucleosides.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063477-04
Application #
2895111
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
1996-08-01
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Ye, Deyong; Shi, Qian; Leung, Chung-Hang et al. (2012) Antitumor agents 294. Novel E-ring-modified camptothecin-4?-anilino-4'-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents. Bioorg Med Chem 20:4489-94
Zhang, Wei; Dutschman, Ginger E; Li, Xin et al. (2011) Quantitation of paclitaxel and its two major metabolites using a liquid chromatography-electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 879:2018-22
Leung, Chung-Hang; Chan, Daniel Shiu-Hin; Man, Bradley Yat-Wah et al. (2011) Simple and convenient G-quadruplex-based turn-on fluorescence assay for 3' ? 5' exonuclease activity. Anal Chem 83:463-6
Zhang, Wei; Tan, Shenglan; Paintsil, Elijah et al. (2011) Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique. Biochem Pharmacol 82:411-7
Hu, Rong; Lam, Wing; Hsu, Chih-Hung et al. (2011) UMP/CMPK is not the critical enzyme in the metabolism of pyrimidine ribonucleotide and activation of deoxycytidine analogs in human RKO cells. PLoS One 6:e19490
Hines, John; Ju, Rong; Dutschman, Ginger E et al. (2010) Reversal of TNP-470-induced endothelial cell growth arrest by guanine and guanine nucleosides. J Pharmacol Exp Ther 334:729-38
Wang, Ying; Gao, Wenli; Svitkin, Yuri V et al. (2010) DCB-3503, a tylophorine analog, inhibits protein synthesis through a novel mechanism. PLoS One 5:e11607
Zhang, Wei; Dutschman, Ginger E; Li, Xin et al. (2009) Quantitation of Irinotecan and its two major metabolites using a liquid chromatography-electrospray ionization tandem mass spectrometric. J Chromatogr B Analyt Technol Biomed Life Sci 877:3038-44
Lam, Wing; Bussom, Scott; Cheng, Yung-Chi (2009) Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma. Mol Cancer Ther 8:415-23
McNeill, Daniel R; Lam, Wing; DeWeese, Theodore L et al. (2009) Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res 7:897-906

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