The objective of this proposal is to identify biochemical parameters and relationships that are associated with the cytotoxicity of a variety of nucleoside analogs. These factors will be monitored in tumor cells and host mouse tissues in order to develop a rational basis for drug dose levels and schedules of administration that would produce the maximal therapeutic benefit in model systems. The compounds of interest are: arabinosyladenine, arabinosyl-1-fluoroadenine, arabinosylcytosine, xylosyladenine, and 2'-deoxyribosyl-2-chloroadenine. Biochemical parameters to be studied that reflect the action of these drugs are: formation and retention of the active nucleoside triphosphate metabolites, the effects of these triphosphates on cellular macromolecular synthesis, the activities of specific enzymes and enzymatic processes, interactions with natural nucleotides, incorporation into nucleic acids and the induction of aberrations in nucleic acid synthesis. The ultimate goal of this project is to develop and understanding of the biochemical and pharmacological basis for successful experimental chemotherapy. This knowledge could form the foundations upon which the rational construction of protocols for clinical trial of these and other drugs studied in a similar manner will be built.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028596-06
Application #
3168229
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1980-08-01
Project End
1987-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2018) Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations. Cancer Chemother Pharmacol 81:255-267
Al Abo, Muthana; Sasanuma, Hiroyuki; Liu, Xiaojun et al. (2017) TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors. Mol Cancer Ther 16:2543-2551
Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2016) Mechanism-Based Drug Combinations with the DNA Strand-Breaking Nucleoside Analog CNDAC. Mol Cancer Ther 15:2302-2313
Lai, Tsung-Huei; Ewald, Brett; Zecevic, Alma et al. (2016) HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia. Clin Cancer Res 22:3537-49
Liu, Xiao-Jun; Nowak, Billie; Wang, Ya-Qing et al. (2012) Sapacitabine, the prodrug of CNDAC, is a nucleoside analog with a unique action mechanism of inducing DNA strand breaks. Chin J Cancer 31:373-80
Liu, Xiaojun; Kantarjian, Hagop; Plunkett, William (2012) Sapacitabine for cancer. Expert Opin Investig Drugs 21:541-55
Guo, Lei; Liu, Xiaojun; Jiang, Yingjun et al. (2011) DNA-dependent protein kinase and ataxia telangiectasia mutated (ATM) promote cell survival in response to NK314, a topoisomerase II? inhibitor. Mol Pharmacol 80:321-7
Zecevic, Alma; Sampath, Deepa; Ewald, Brett et al. (2011) Killing of chronic lymphocytic leukemia by the combination of fludarabine and oxaliplatin is dependent on the activity of XPF endonuclease. Clin Cancer Res 17:4731-41
Liu, Xiaojun; Wang, Yaqing; Benaissa, Sherri et al. (2010) Homologous recombination as a resistance mechanism to replication-induced double-strand breaks caused by the antileukemia agent CNDAC. Blood 116:1737-46
Wang, Yaqing; Liu, Xiaojun; Matsuda, Akira et al. (2008) Repair of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine-induced DNA single-strand breaks by transcription-coupled nucleotide excision repair. Cancer Res 68:3881-9

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