The Roswell Park Memorial Institute and Gastrointestinal Tumor Study Group Phase III Experience with the Modulation of 5-Fluorouracil by Leucovorin in Metastatic Colorectal Adenocarcinoma

The therapeutic activity of 5-Fluorouracil (5-FU) in gastrointestinal (GI) malignancies may be enhanced by increasing the tumor cell reduced folate pools in vivo 1, 2, 3, 4. One of the mechanisms of action of 5-FU is its conversion into fluorodexoyuridylate (FdUMP), which inhibits thymidylate synthetase (TS) 5. FdUMP binds tightly to TS in the presence of the cofactor L-5, 10-methylene tetrahydrofolate (CH2FH4). This interaction of FdUMP and TS leads to the formation of a covalent ternary complex, TS-CH2FH4-FdUMP6. The stability of the ternary complex is maximal when the extracellular folate concentration is 10 umol/L in cell culture7. Therefore, high levels of inhibition of TS and a slow recovery of the enzyme activity can occur only in the presence of sufficient intracellular concentrations of reduced folates.