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.
KeywordsRoswell Park Memorial Institute Intravenous Hydration Thymidylate Synthetase Metastatic Colorectal Carcinoma Fatal Toxicity
Unable to display preview. Download preview PDF.
- 5.C. Heidelberger, Fluorinated pyrimidines and their nucleosides, in: “Handbook of Experimental Pharmacology, Antineoplastic and Immunosuppressive Agents”, A. C. Sartorelli and D. G. Johns, eds., Springer Verlag, New York (1975).Google Scholar
- 7.R. M. Evans, J. D. Laskin and M. T. Hakala, Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil, Cancer Res. 41: 3283 (1981).Google Scholar
- 8.N. Petrelli, L. Herrera, Y. Rustum, P. Burke, P. Creaven, J. Stulc, L. Emrich and A. Mittelman, A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma, J. Clin. Oncol. 5: 10: 1559 (1987).PubMedGoogle Scholar
- 12.P. F. Engstrom, J. M. Maclntyre, A. Mittelman, et al., Chemotherapy of advanced colorectal carcinoma: Fluorouracil alone vs two drug combinations using fluorouracil, hydroxyurea, semustine, decarbazine, razoxane and mitomycin: A phase III trial by the Eastern Cooperative Oncology Group, Am. J. Clin. Oncol. 7: 313 (1984).PubMedCrossRefGoogle Scholar
- 14.F. Trave, Y. M. Rustum, N. J. Petrelli, L. Herrera, A. Mittelman, C. Frank and P. J. Creaven, Plasma and tumor tissue pharmacology of high dose intravenous 5-formyltetrahydrofolate inhibition with 5-fluorouracil in patients with advanced colorectal carcinoma, J. Clin. Oncol. in press (1988).Google Scholar
- 16.N. Petrelli, D. Stablein, H. Bruckner, A. Megibow, R. Mayer and H. Douglass, A prospective randomized phase III trial of 5-fluorouracil (5FU) versus 5FU and high dose leucovorin (HDCF) versus 5FU and low dose leucovorin (LDCF) in patients (pts) with metastatic colorectal carcinoma: A report of the Gastrointestinal Tumor Study Group, Proc. Am. Assoc. Cancer Pes. 7: p. 94 (abst. No. 357 ) (1988).Google Scholar