Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase
- 15 March 1989
- Vol. 63 (S6) , 1008-1012
- https://doi.org/10.1002/1097-0142(19890315)63:6+<1008::aid-cncr2820631303>3.0.co;2-z
Abstract
Exposure of tumor cells to reduced folates before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro-2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests that the mechanism of this synergism is a kinetic stabilization of complex formed between thymidylate synthase and fluorodeoxyuridylate that also involves a mole of the cofactor for the thymidylate synthase reaction, 5,10-methylenetetrahydrofolate. This effect results in an extended time of depletion of thymidine nucleotides with a resultant increased level of cell death. The biochemical aspects of this interaction are discussed and related to the therapeutics of this combination.Keywords
This publication has 16 references indexed in Scilit:
- Overview of clinical trials using 5-fluorouracil and leucovorin for the treatment of colorectal cancerCancer, 1989
- Chemotherapy of advanced colorectal carcinomaAmerican Journal of Clinical Oncology, 1984
- Prospective randomized reappraisal of 5-fluorouracil in metastatic colorectal carcinoma a comparative trial with 6-thioguanineCancer, 1984
- Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetaseBiochemical Pharmacology, 1981
- Survival and response to chemotherapy for advanced colorectal adenocarcinoma. An eastern cooperative oncology group reportCancer, 1980
- Biochemical determinants of tumor sensitivity to 5-fluorouracil: Ultrasensitive methods for the determination of 5-fluoro-2′-deoxyuridylate, 2′-deoxyuridylate, and thymidylate synthetaseProceedings of the National Academy of Sciences, 1979
- Effect of 5,10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2'-deoxyuridylate from thymidylate synthetase: evidence for an ordered mechanismBiochemistry, 1978
- Cytotoxicity of 5-fluoro-2'-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate.Proceedings of the National Academy of Sciences, 1978
- Fluorinated pyrimidines. Structures of reversible and irreversible complexes of thymidylate synthetase and fluorinated pyrimidine nucleotidesBiochemistry, 1974
- Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylateBiochemistry, 1974