Distribution and Metabolism of Calcium Leucovorin in Normal and Tumor Tissue
Thymidylate synthase catalyzes the formation of thymidylate from deoxyuridine monophosphate in a reaction which employs the folate cofactor CH2-H4PteGlu both as methyl donor and reductant. The TS inhibitor FUra has been widely used clinically for the treatment of solid tumors, particularly colorectal carcinomas. Inhibition of TS by FUra occurs following its metabolism to FdUMP and formation of a ternary complex involving TS, FdUMP and CH2-H4PteGlu (1–3). An increased interest in the use of FUra stems from the observations in tissue culture (4, 5) and in extracts of human colon adenocarcinoma xenographs (6) that the antitumor effects of FUra can be potentiated by the administration of exogenous folates in the form of calcium leucovorin. The results of these studies indicated that the response of many tumors to FUra is limited by the intracellular concentration of CH2-H4PteGlu and that the metabolism of 5-CHO-H4PteGlu to CH2-H4PteGlu following cellular uptake expands this cofactor pool. With increased intracellular levels of CH2-H4PteGlu, the half-life of the ternary complex is increased, resulting in increased cytoxicity. In support of this model, enlargement of the CH2-H4PteGlu pool following administration of 5-CHO-H4PteGlu has been demonstrated in tissue culture (7).
KeywordsSodium Ascorbate Plasma Folate Thymidylate Synthetase Total Folate Tetrahydrofolic Acid
Unable to display preview. Download preview PDF.
- 10.D. Machover, L. Schwarzenberg, E. Goldschmidt, J.M. Tourane, B. Michalski, M. Hatat, T. Dorval, J.L. Misset, C. Jasmin, R. Maral, and G. Mathe’, Treatment of Advanced Colorectal and Gastric Adenocarcinomas with 5-Fluorouracil Combined with High-Dose Folinic Acid: A Pilot Study. Cancer Treatment Rep. 66: 1803 (1982).Google Scholar
- 11.J.C. Grem, D.F. Hoth, J.M. Hamilton, S.A. King, and B. Leyland-Jones, Overview of Current Status and Future Direction of Clinical Trials with 5-Fluorouracil in Combination with Folinic Acid, Cancer Treatment Rep. 71: 1241 (1987).Google Scholar
- 18.N.R. Meija, and R.E. MacKenzie, NAD-Dependent Methylenetetrahydrofolate Dehydrogenase Is Expressed by Immortal Cells, J. Biol. Chem. 260: 14616 (1985).Google Scholar
- 21.B. McGuire, L. Sia, P. Leese, M. Gutierrez, and E.L.R. Stokstad, Pharmacokinetics of Leucovorin Calcium Given Intravenously, Intramuscularly, and Orally to Human Subjects, In NCI Monograph “Development of Folates and Folic Acid Antagonists in Cancer Chemotherapy”, p. 47, (1987).Google Scholar
- 22.F.M. Sirotnak, P.L. Chello, D.M. Moccio, R.L. Kisluk, G. Combepine, Y. Gaumont, and J.A. Montgomery, Stereospecificity at Carbon 6 of Formyltetrahydrofolate as a Competitive Inhibitor of Transport and Cytotoxicity of Methotrexate in vitro, Biochem. Pharmacol. 28: 2993 (1979).PubMedCrossRefGoogle Scholar