PHASE I TRIAL OF D1694, AN INHIBITOR OF THYMIDYLATE SYNTHASE

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This phase I study is designed to define the MTD (maximum tolerated dose) of D1694 in pediatric patients. Analogs of folic acid have been successfully used for the treatment of cancer for more than 40 years. The underlying mechanism of action for classial antifols such as methotrexate (MTX) is their ability to block the denovo synthesis of purine and pyrimidine nucleotide precursors of DNA, primarily by inhibiting dihydrofolate reductase (DHFR). Thymidylate synthase (TS), an enzyme which acts by utilizing 5, 10-CH2FH4 in the reductive methylation of deoxyuridylate (dUMP), is required for the de novo synthesis of thymidylate and is thus a potential target of folic acid analogs.