Abstract

The further characterization and study of 3 important enzymes that are targets for chemotherapeutic agents is proposed. By using techniques of recombinant DNA technology, we propose to generate sufficient amounts of two of these enzymes (dihydrofolate reductase and thymidylate synthase) and altered forms of these enzymes for detailed studies of structure, characterization, and interaction with inhibitors. The regulation of thymidylate synthetase will be further studied. Based on this and other information, new approaches to drug development, in particular inhibition of polyglutamate synthetase are planned. Strategies for prevention and eradication of drug resistant cells, based on concurrent or alternating therapy with folate contagonists have been formulated, and will be tested using tumor cells propagated in vitro, and with murine tumors propagated in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA008010-21
Application #
3163291
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1963-09-01
Project End
1989-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
21
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code

  Publications

Hsieh, Yi-Ching; Tedeschi, Philip; Adebisi Lawal, Rialnat et al. (2013) Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs. Mol Pharmacol 83:339-53
Xie, Xiaoqi; Kerrigan, John E; Minko, Tamara et al. (2013) Antitumor and modeling studies of a penetratin-peptide that targets E2F-1 in small cell lung cancer. Cancer Biol Ther 14:742-51
Roussel, Breton; Johnson-Farley, Nadine; Kerrigan, John E et al. (2012) A second target of benzamide riboside: dihydrofolate reductase. Cancer Biol Ther 13:1290-8
Hsieh, Yi-Ching; Skacel, Nancy E; Bansal, Nitu et al. (2009) Species-specific differences in translational regulation of dihydrofolate reductase. Mol Pharmacol 76:723-33
Mishra, Prasun J; Menon, Lata G; Mishra, Pravin J et al. (2009) Translational modulation of proteins expressed from bicistronic vectors. Mol Imaging 8:305-18
Capiaux, Gina M; Budak-Alpdogan, Tulin; Alpdogan, Onder et al. (2004) Protection of hematopoietic stem cells from pemetrexed toxicity by retroviral gene transfer with a mutant dihydrofolate reductase-mutant thymidylate synthase fusion gene. Cancer Gene Ther 11:767-73