Abstract
Leucovorin is a pharmaceutical preparation containing a mixture of the natural and unnatural diastereomers of 5-formyl-tetrahydrofolate (N5-HCO-H4PteGlu). All reduced folates have an S chirality at the 6 carbon of the tetrahydropterine ring and the natural and unnatural isomers of 5-formyltetrahydro-folate are designated respectively as (6S)- and (6R)-N 5 -HC0-H4PteGlu1–4. After being used for many years as a rescue agent following high doses of the antifolate methotrexate (MTX) 5, leucovorin is now also administered clinically in combination with 5-fluorouracil (5-FU) to enhance its antitumor activity, an effect dependent on the replenishment of intracellular folate pools by the reduced folate 6,7. Following intravenous leucovorin administration, the 6S isomer disappears rapidly from plasma with a mean elimination half-life of 20 to 30 minutes while the 6R compound has a much slower clearance (half-lives of 7.5 to 11 hours) and persists at high concentrations for prolonged periods 6,8. Consequently, the possible interactions between the natural and unnatural N5-HCO-H4PteGlu isomers have been studied both experimentally and in the clinic. This paper will summarize available data on the isomers’ cellular interactions.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
H.E. Sauberlich and C.A. Baumann. A factor required for the growth of Leuconostoc citrovorum. J Biol Chem 176s 165–173 (1948).
T.J. Bond, T.J. Bardos, M. Sibley, W. Shive. The folinic acid group, a series of new vitamins related to folic acid. J. Amer Chem Soc 74: 3852–3853 (1949).
D.B. Cosulish, J.M. Smith, H.P. Broquist. Diastereomer of leucovorin. J Amer Chem Soc 74: 4215–4216 (1952).
J.C. Fontecilla-Camps, C.E. Bugg, C. Temple, J.C. Rose, J.A. Montgomery, R.L. Kisliuk. Absolute configuration of biological tetrahydrofolate. A crystallo-graphic determination. J Amer Chem Soc 101: 6114–6115 (1979).
J. Jolivet, K.H. Cowan, G.A. Curt, N.J. Clendeninn, B.A. Chabner. The pharmacology and clinical use of methotrexate. N Engl J Med 309: 1094–1104 (1983).
D. Machover, E. Goldschmidt, P. Chollet, G. Metzger, J. Zittoun, J. Marquet, J.M. Vandenbulcke, J.L. Misset, L. Scharzenberg, J.B. Fourtillan, H. Gaget, G. Mathe. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4: 685–696 (1986).
B. Ullman, M. Lee, D.W. Martin Jr, D.V. Santi. Cytotoxicity of 5-fluoro-2′-deoxyuridine: Requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA 75: 980–983 (1978).
J.A. Straw, D. Szapary, W.T. Wynn. Pharmacokinetics of the diastereomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res 44: 3114–3119 (1984).
F.M. Sirotnak, P.L. Chello, D.M. Moccio, R.L. Kisliuk, G. Combepine, Y. Gaumont, J.A. Montgomery. Stereospecificity at carbon 6 of formyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexate in vitro. Biochem Pharmacol 28: 2993–2997 (1979).
R. Bertrand and J. Jolivet. Lack of interference by the unnatural isomer of 5-formyltetrahydrofolate in leucovorin preparations. J Natl Cancer Inst. 81: 1175–1178 (1989).
G.B. Henderson, J.M. Tsuji, H.P. Kumar. Characterization of the individual transport routes that mediate the influx and efflux of methotrexate in CCRF-CEM human lymphoblastic cells. Cancer Res 46: 1633–1638 (1986).
R.L. Shilsky, G.B. Kay and K.E. Choi. Uptake and biological activity of the stereoisomers of leucovorin in human colon cancer cells. Proc Annu Meet Am Assoc Cancer Res 29: A1989 (1988).
R. Bertrand, R.E. MacKenzie and J. Jolivet. Human liver methenyltetrahydrofolate synthetases improved purification and increased affinity for folate polyglutamate substrates. Biochim Biophys Acta 911: 154–161 (1987).
P.P. Lee and R.L. Schilsky. Inhibition of thymidylate synthase by the diastereoisomers of leucovorin. Cancer Chemoth Pharmacol 26: 273–277 (1990).
J.K. Sato and R.G. Moran. Interaction of methotrexate and citrovorum factor at folylpolyglutamate synthetase. Proc Annu Meet Am Assoc Cancer Res 25: A1234 (1984).
D.M. Boarman and C.J. Allegra. Intracellular metabolism of 5-formyltetrahydrofolate in human breast and colon cell lines. Cancer Res 52: 36–44 (1992).
J.J. McGuire and C.A. Russell. Biological and biochemical properties of the natural (6S) and unnatural (6R) isomers of leucovorin and their racemic (6R,S) mixture. J Cell Pharmacol 2: 317–323 (1991).
Z.-G. Zhang and Y.M. Rustum. Effects of diastereoisomers of 5-formyltetrahydrofolate on cellular growth, sensitivity to 5-fluoro-2′-deoxyuridine, and methenyltetrahydrofolate polyglutamate levels in HCT-8 cells. Cancer Res 51: 3476–3481 (1991).
C. Temple Jr, J.D. Rose, W.R. Laster and J.A. Montgomery. Reversal of methotrexate toxicity in mice by a calcium salt of citrovorum facor and related compounds. Cancer Treat Rep 65: 1117–1119 (1981).
S. Bernard, M.C. Etienne, J.L. Fischel. P. Formento and G. Milano. Critical factors for the reversal of methotrexate cytotoxicity by folinic acid. Br J Cancer 63: 303–307 (1991).
J. Zittoun, J. Marquet, J.J. Pilorquet, C. Tonetti, E. De Gialluly. Comparative effect of 6S, 6R and 6RS leucovorin on methotrexate rescue and on modulation of 5-fluorouracil. Br J Cancer 63: 885–888 (1991).
K.E. Choi, R.L. Schilsky, S.C. McGrath, C.A. VanKast. Purification and biological activity of the steroisomers of leucovorin. Proc Annu Meet Am Assoc Cancer Res 28: A1089 (1987).
M.-C. Etienne, A. Thyss, Y. Bertrand, R. Touraine, H. Rubie, A. Robert, G. Milano. 1-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children. J Natl Cancer Inst 84: 1190–1195 (1992).
E. Mini, B.A. Moroson, J.R. Bertino. Cytotoxicity of floxuridine and 5-fluorouracil in human T-lymphoblast leukemia cells: enhancement by leucovorin. Cancer Treat Rep 71: 381–389 (1987).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media New York
About this chapter
Cite this chapter
Jolivet, J., Bertrand, R. (1993). Cellular Interactions Between the Natural and Unnatural Isomers of 5-Formyltetrahydrofolate. In: Rustum, Y.M. (eds) Novel Approaches to Selective Treatments of Human Solid Tumors. Advances in Experimental Medicine and Biology, vol 339. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2488-5_3
Download citation
DOI: https://doi.org/10.1007/978-1-4615-2488-5_3
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6060-5
Online ISBN: 978-1-4615-2488-5
eBook Packages: Springer Book Archive