This application is for continuation of a comprehensive program involving design, synthesis, biological evaluation in vitro and in vivo against murine tumors and human tumor xenografts, biochemical screening and in- depth investigations of mechanism of action of new anticancer agents of the following classes; analogs of purines and pyrimidines and their nucleosides and nucleotides and analogs of penclomedine, a new agent entering phase I clinical trials for breast cancer. New agents will be evaluated for cytotoxicity in vitro against a panel of human solid tumors and leukemias and murine tumors, and nucleoside analogs will be investigated for biochemical effects against a series of enzymes involved in purine, pyrimidine, and nucleic acid metabolism. Agents of interest will be evaluated in vivo against selected murine tumors and human tumor xenografts and also subjected to in-depth biochemical studies on their mechanism of action. Agents determined to be of clinical potential will be evaluated against additional tumor models. The results of the biological and biochemical investigations will be used to guide synthesis projects with respect to selection of agents that merit further study and the design of new agents on the basis of observations on structure-activity relationships and mechanisms of action. Specifically, three synthesis- biochemistry projects will provide new agents for biochemical and biological evaluations and investigations, and the core components will provide preparative-scale synthesis and analytical services, chemotherapy evaluations in vitro and in vivo and elementary toxicology evaluation, and screening against a panel of enzymes involved in nucleic acid metabolism, resulting in a unified and interrelated program of drug development.
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 |
Zhang, Yan; Secrist 3rd, John A; Ealick, Steven E (2006) The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation. Acta Crystallogr D Biol Crystallogr 62:133-9 |
Struck, Robert F; Waud, William R (2006) Thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of demethylpenclomedine as novel anticancer agents. Cancer Chemother Pharmacol 57:180-4 |
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