The goal of this proposal is to gain an understanding of the biochemical and molecular basis for the cytotoxic action of three clinically effective nucleoside analogues. The application focuses upon the cellular pharmacology and molecular action of arabinosylcytosine (ara-C), arabinsoyladenine (ara-A) and arabinosyl 2-fluoroadenine (F-ara-A). Correlations will be sought between the cellular concentrations of the active arabinosyl triphosphates and the corresponding deoxynucleoside triphosphate for evidence of a competitive relationship in the inhibition of DNA synthesis. The effects of arabinosyl nucleotides on the deoxynucleotide levels in synchronous cell populations will be evaluated to test the hypothesis of """"""""self-potentiation"""""""" as applied to ara-A and F-ara-A. The quantitative relationship between cytotoxicity and incorporation of arabinosyl nucleotides into DNA will be studied and compared to determine whether incorporation of a certain number of arabinosyl residues will elicit a defined cytotoxic effect. The mutagenic action of arabinosyl nucelosides will be compared and the genetic bases for observed mutations will be sought. The incorporation of F-ara-A into RNA will be characterized and the consequences to transcription and translation of a specific gene will be studied. Finally, the ability of arabinosyl nucleosides to inhibit the repair of drug-induced DNA damage will be correlated with their cellular metabolism and the consequences of this inhibition for cytotoxicity will be considered.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028596-10
Application #
3168232
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1980-08-01
Project End
1992-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Other Domestic Higher Education
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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