Abstract

The long-term goal of this project remains the development of new agents for the treatment of human cancers. Since most, if not all, of the nucleosides currently in use for the treatment of human cancers must phosphorylated to their active forms, we plan to investigate in some detail the enzymes that are known to carry out this activation. Deoxycytidine kinase is the primary, but not the only, enzyme that initiates this activation process, so we plan to focus on it, in collaboration with Dr. Donna S. Shewach of the University of michigan. We plan to prepare a broad series of compounds with a focus on them activating enzymes as well as their antitumor selectivity. We also plan to examine our collection of nucleoside triphosphates as inhibitors of telomerase, a DNA polymerase which is activated in human cancers. The studies will show triphosphates we have on hand or easily generate, and will provide us with SAR information that will be used in designing new compounds that will be more specific inhibitors for this enzyme, which appears to be an important new target for can chemotherapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA034200-13A1
Application #
5207198
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1996
Total Cost
Indirect Cost

  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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