Abstract

The overall goal of the program project is to design and synthesize new drugs for the treatment of cancer. The goal of this """"""""Mechanism of action of nucleoside analogs"""""""" is to perform experiments to characterize the biochemical pharmacology of the new compounds that will be synthesized in projects 2 and 4. The information that will be gained about the mechanism of action of these compounds is vital to the rational development of these compounds as anticancer agents. In addition, this information will be provided to the organic chemists in projects 2 and 4 during regular group meetings to be used in the rational design of new agents. This project has 3 specific aims. In the first aim we will evaluate all compounds for toxicity to CEM cells to identify active and inactive agents. In the second aim we will perform biochemical experiments on selected compounds to gain a preliminary understanding of their mechanism of action. In the third aim, we will perform extensive studies on compounds that warrant a more thorough evaluation. Studies are planned to characterize in detail the mechanism of action of 2 agents that have demonstrated excellent in vivo antitumor activity, 4'-thio-arabinofuranosylcytosine and 2-Cl-2'-F-2'-deoxy- arabinofuranosyladenine (Clofarabine). These studies should lead to a comprehensive understanding of the mechanism of action of new agents that will aid in their development by determining how these compounds differ form existing anticancer drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA034200-18
Application #
6483136
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
1986-04-01
Project End
2006-01-31
Budget Start
Budget End
Support Year
18
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205

  Publications

Thottassery, Jaideep V; Sambandam, Vijaya; Allan, Paula W et al. (2014) Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4'-thio-2'-deoxycytidine and 5-aza-4'-thio-2'-deoxycytidine. Cancer Chemother Pharmacol 74:291-302
Waud, William R; Parker, William B; Gilbert, Karen S et al. (2012) Isolation and characterization of a murine P388 leukemia line resistant to thiarabine. Nucleosides Nucleotides Nucleic Acids 31:14-27
Waud, William R; Gilbert, Karen S; Secrist 3rd, John A (2012) Preclinical antitumor activity of thiarabine in human leukemia and lymphoma xenograft models. Nucleosides Nucleotides Nucleic Acids 31:647-60
Waud, William R; Gilbert, Karen S; Secrist 3rd, John A (2012) Preclinical combination therapy of thiarabine plus various clinical anticancer agents. Nucleosides Nucleotides Nucleic Acids 31:630-46
Waud, William R; Gilbert, Karen S; Secrist 3rd, John A (2011) Lack of in vivo cross-resistance with 4'-thio-ara-C against drug-resistant murine P388 and L1210 leukemias. Cancer Chemother Pharmacol 68:399-403
Waud, William R; Gilbert, Karen S; Parker, William B et al. (2011) Isolation and characterization of a murine P388 leukemia line resistant to clofarabine. Nucleosides Nucleotides Nucleic Acids 30:826-38
Parker, William B; Shaddix, Sue C; Gilbert, Karen S et al. (2009) Enhancement of the in vivo antitumor activity of clofarabine by 1-beta-D-[4-thio-arabinofuranosyl]-cytosine. Cancer Chemother Pharmacol 64:253-61
Tiwari, Kamal N; Shortnacy-Fowler, Anita T; Parker, William B et al. (2009) Synthesis and anticancer evaluation of 4'-C-methyl-2'-fluoro arabino nucleosides. Nucleosides Nucleotides Nucleic Acids 28:657-77
Someya, Hitoshi; Waud, William R; Parker, William B (2006) Long intracellular retention of 4'-thio-arabinofuranosylcytosine 5'-triphosphate as a critical factor for the anti-solid tumor activity of 4'-thio-arabinofuranosylcytosine. Cancer Chemother Pharmacol 57:772-80
Thottassery, Jaideep V; Westbrook, Louise; Someya, Hitoshi et al. (2006) c-Abl-independent p73 stabilization during gemcitabine- or 4'-thio-beta-D-arabinofuranosylcytosine-induced apoptosis in wild-type and p53-null colorectal cancer cells. Mol Cancer Ther 5:400-10

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