Abstract

This proposal is for a comprehensive program for the design, synthesis and biochemical-biological study of new anticancer agents of the following types: analogs of purines, pyrimidines, and their nucleosides; pteridines; chemically active agents; and 1-deaza-7,8-dihydropteridines, a new class of antimitotic agents. Newly synthesized agents will be given a preliminary biochemical and biological evaluation to select compounds of promise. Agents that appear of interest will be subject to intensive studies to determine their mechanisms of action, their activities against selected experimental tumors, and their activities against selected viruses; finally, each agent of potential clinical interest will be subjected to preclinial pharmacological evaluation. The results of the biochemical-biological studies will be used to guide the synthetic program with respect to (a) the immediate selection of agents that merit further study; and (b) the design of new agents on the basis of observations on the metabolic properties and structure-activity relationships for inhibition of target enzymes. The biochemical studies will also contribute to the design of treatment regimens that may be made more effective by taking into consideration the biochemical and pharmacological properties of the subject agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA034200-07
Application #
3093541
Study Section
Cancer Therapeutics Program Project Review Committee (CTR)
Project Start
1986-04-01
Project End
1990-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
7
Fiscal Year
1989
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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