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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA008010-24
Application #
3163295
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1987-12-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
24
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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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
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