The fluoropyrimidines are potent inhibitors of the growth of human and murine tumor cells in culture and of a spectrum of mouse tumors in vivo but have limited activity against human tumors in clinical circumstances. Previous studies have suggested that the activity of these compounds as inhibitors of thymidylate synthase (and, hence, of DNA synthesis) is limited in human tumors by rapid accumulation of deoxyuridylate and by the low availability of folate cofactors. This research program would study the factors that limit and control tumor cell death with fluoropyrimidines and other inhibitors of thymidylate synthase and determine how these factors differed in mouse and human cells. Inhibition of thymidylate synthase would be studied and related to deoxyuridylate accumulation and 5,10-methylenetetrahydrofolate pools. The rate of cell kill would be composed in mouse and human cells at sustained equivalent inhibition of thymidylate synthesis using fluoropyrimidine exposure of wild type cells and thymine deprivation of genetic mutants lacking enzyme. The chemotherapeutic activity of combination of fluoropyrimidine with folinic acid, with inhibitors of deoxyuridylate synthesis and with new inhibitors of folate metabolism will be studied using cells in culture and murine tumors in vivo. These studies seek to understand why the activity of the flyoropyrimidines to mouse and human tumors differ and whether the selective cytotoxicity of the fluoropyrimidines can be extended by combination with other agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036054-05
Application #
3173558
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1983-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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Moran, R G; Keyomarsi, K; Patel, R (1988) Tumor cell responses to inhibition of thymidylate synthase. Adv Exp Med Biol 244:71-83
Keyomarsi, K; Moran, R G (1988) Mechanism of the cytotoxic synergism of fluoropyrimidines and folinic acid in mouse leukemic cells. J Biol Chem 263:14402-9
Moran, R G; Keyomarsi, K (1987) Biochemical rationale for the synergism of 5-fluorouracil and folinic acid. NCI Monogr :159-63
Keyomarsi, K; Moran, R G (1986) Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res 46:5229-35

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