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.
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