The overall aim of this proposal is the development of deoxynucleoside analogs for the treatment of cancer. This includes studies on the mechanism of action and resistance of novel nucleoside analogs as well as the exploration of novel strategies to use nucleoside analogs effectively against cancer. Our studies will center on one compound discovered by this laboratory: Troxacitabine (L-OddC), a novel L-configuration anticancer deoxycytidine (dCyd) analog that is currently under phase III clinical trial.
The aim will be to study the biochemical determinants of L-OddC that allow sufficient activation of this poorly phosphorylated analog in the presence of much higher concentrations of naturally occurring cytidine (Cyd) nucleotides and to understand how L-OddC exerts its action, as well as explore a novel strategy to use it more effectively. The structure of L-OddC together with Gemcitabine (dFdC), a D-configuration deoxycytidine analog, is shown in Figure 1.
Specific Aims are listed as follows: 1. To examine the role of CMP/UMP kinase in the phosphorylation of L-OddCMP and dFdCMP. 2. To examine the role of Hypoxia: a. in regulating phosphoglycerate kinase (PGK), which is responsible for the phosphorylation of L- OddCDP to L-OddCTP. b. in cytotoxicity of L-OddC, the formation of L-OddCTP and incorporation of L-OddC into DNA. 3. To examine the impact of the antiangiogenesis compound, thalidomide on the: a. Antitumor activity of L-OddC. b. Expression of PGK and Apurinic/apyrimidic endonuclease -1 (APE-1) in tumor. The proposed studies are based on original findings in this laboratory. It should yield novel information for understanding the biochemical determinants of the action of L-OddC, the biochemistry of the enzymes studied and possible novel use of L-OddC for the treatment of solid tumor.
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|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|
|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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