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Leucovorin as a Prodrug

  • D. G. Priest
  • J. C. Schmitz
  • T. Walle
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 339)

Abstract

To exert its antitumor effects, leucovorin must ultimately become activated by conversion to CH2FH4.* Elevation of this reduced folate cofactor stabilizes the inhibitory ternary complex formed between the FU active metabolite, FdUMP and thymidylate synthase, resulting in suppression of DNA synthesis or repair.1–4 It has been demonstrated both in animal models5 and in humans6 that administration of leucovorin results in intratumor elevation of CH2FH4 and the closely related reduced folate, FH4. However, precisely when and where the metabolic activity causing this elevation occurs remains in question. Further, while enzyme activities have been reported7–9 that could sustain the interconversions shown below, the precise metabolic pathways used have not been defined.

Keywords

Folinic Acid Thymidylate Synthetase Total Folate Advanced Colorectal Carcinoma Leucovorin Calcium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    P.V. Danenberg and K.D. Danenberg, Effect of 5, 10-methylene-tetrahydrofolate on the dissociation of 5-fluoro-2′-deoxy-uridylate from thymidylate synthetase: evidence for an ordered mechanism, Biochemistry, 17: 4018 (1978).PubMedCrossRefGoogle Scholar
  2. 2.
    B. Ullman, M. Lee, and D.W. Martin, Jr, et al., Cytotoxicity of 5-fluoro-2′-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate, Proc. Natl. Acad. Sci., 75: 980 (1978).PubMedCrossRefGoogle Scholar
  3. 3.
    J.A. Houghton, C. Schmit, and P.J. Houghton, The effects of derivatives of folic acid on the fluorodeoxyuridylate thymidylate synthetase covalent complex in human colon xenografts, Eur. J. Can. Clin. Oncol., 18: 347 (1982).CrossRefGoogle Scholar
  4. 4.
    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: 3288 (1981).PubMedGoogle Scholar
  5. 5.
    J.A. Houghton, L.G. William, and S.S. DeGraaf, et al., Relationship between dose rate of 6[RS]leucovorin administration, plasma concentrations of reduced folates, and pools of 5, 10-methy-lenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts, Cancer Res., 50: 3493 (1990).PubMedGoogle Scholar
  6. 6.
    F. Trave, Y.M. Rustum, and N.J. Peterelli, Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluororouracil in patients with advanced colorectal carcinoma, J. Clin. Oncol., 6: 1184 (1988).PubMedGoogle Scholar
  7. 7.
    S. Hopkins and L.V., 5, 10-methenyltetrahydrofolate synthetase. Purification and properties of the enzyme from rabbit liver, J. Biol. Chem., 259: 5618 (1984).PubMedGoogle Scholar
  8. 8.
    RE. MacKenzie, Biogenesis and interconversion of substituted tetrahydrofolates, in: “Folates and Pterins”, R.L. Blakley and S.J. Benkovic, eds., Wiley-Interscience, New York (1984).Google Scholar
  9. 9.
    L.V. Schirch, Folates in serine and glycine metabolism, in: “Folates and Pterins”, RL. Blakley and S.J. Benkovic, eds., Wiley-Interscience, New York (1984).Google Scholar
  10. 10.
    B. Ullman, M. Lee, D.W. Martin, Jr., and D.V. Santi, Cytotoxicity of 5-fluoro-2′-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate, Proc. Natl Acad. Scl.U.S.A. 75: 980 (1978).CrossRefGoogle Scholar
  11. 11.
    R.M. Evans, J.D. Laskin, and M.T. Hakala, Effects of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil, Cancer Res. 41: 3288 (1981).PubMedGoogle Scholar
  12. 12.
    E. Mini, T. Mazzei, M. Coronnello, L. Criscuoli, M. Gualtieri, P. Periti, and J.R. Bertino, Effects of 5-methyltetrahydrofolate on the activity of fluoropyrimydines against human leukemia (CCRF-CEM) cells, Biochem. Pharmac., 36: 2905 (1987).CrossRefGoogle Scholar
  13. 13.
    R.J. Mullin, B.R Keith, and D.S. Duch, Distribution and metabolism of calcium leucovorin in normal and tumor tissue, in: “The expanding role of folate and fluoropyrimidines in cancer chemotherapy”, Y. Rustum and J.J. McGuire, eds., Plenum Press, New York (1988).Google Scholar
  14. 14.
    R. Bertrand, R.E. Mackenzie, and J. Jolivet, Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutmate substrates, Biochim. Biophys. Acta. 911: 154 (1987).PubMedCrossRefGoogle Scholar
  15. 15.
    R.G. Matthews, Methylenetetrahydrofolate reductase from pig liver, Methods Enzymol., 122: 372 (1986).PubMedCrossRefGoogle Scholar
  16. 16.
    F.M. Huennekens and K.G. Scrimgeor, N-10-formyltetrahydrofolic deacylase, Methods Enzymol., 6: 373 (1963).CrossRefGoogle Scholar
  17. 17.
    M.S. Bunni and D.G. Priest, Human red blood cell-mediated metabolism of leucovorin [(R,S)5-formyltetrahydrofolate], Arch. Biochem. Biophys., 286: 633 (1991).PubMedCrossRefGoogle Scholar
  18. 18.
    V.M. Whitehead, R. Pratt, A. Viallet, and B.A. Cooper, Intestinal conversion of folinic acid to 5-methyltetrahydrofolate in man, Br. J. Haematol, 22: 63 (1972).PubMedCrossRefGoogle Scholar
  19. 19.
    J.A. Straw, D. Szapary, and W.T. Wynn, Pharmacokinetics of the diastereomers of leucovorin after intravenous and oral administration to normal subjects, Cancer Res., 44: 3114 (1984).PubMedGoogle Scholar
  20. 20.
    R.L. Schilsky and M.J. Ratain, Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administrations, J. Natl Cancer Inst., 82: 1411 (1990).PubMedCrossRefGoogle Scholar
  21. 21.
    A. Schalhorn, M. Kühl, and G. Stupp-Poutot, et al., Pharmacokinetics of reduced folates after short-term infusion of d,l-folinic acid, Cancer Chemother. Pharmacol., 25: 440 (1990).PubMedCrossRefGoogle Scholar
  22. 22.
    B.W. McGuire, L.L. Sia, and J.D. Haynes, et al., Absorption kinetics of orally administered leucovorin calcium, NCI Monogr. 5: 47 (1987).PubMedGoogle Scholar
  23. 23.
    P.O. Greiner, J. Zittoun, and J. Marquet, et al., Pharmacokinetics of (-)-folinic acid after oral and intravenous administration of the racemate, Br. J. Clin. Pharmac., 28: 289 (1989).CrossRefGoogle Scholar
  24. 24.
    J.A. Houghton and L.G. William, et al., Comparison of the conversion of 5-formyltetrahydrofolate and 5-methyltetrahydrofolate to 5, 10-methylenetetrahydrofolates and tetrahydrofolates in human colon tumors, Can. Comm., 1: 167 (1989).Google Scholar
  25. 25.
    D.G. Priest and M.T. Doig, Tissue folate polyglutamate chainlength determination by electrophoresis as thymidylate synthase-fluorodeoxyuridylate ternary complexes, Methods Enzymol., 122: 313 (1986).PubMedCrossRefGoogle Scholar
  26. 26.
    D.G. Priest, J.C. Schmitz, M.A. Bunni, and R.K. Stuart, Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously, J. Natl. Can. Inst., 83: 1806 (1991).CrossRefGoogle Scholar
  27. 27.
    J.C. Schmitz, R.K. Stuart, J.C. Barredo, and D.G. Priest, Interconversion of folates in human plasma and red blood cells, Pro. Am. Asso. Can. Res., 33: 410 (1992).Google Scholar
  28. 28.
    K. Pinter, V.J. Davisson, and D.V. Santi, Cloning, sequencing, and expression of the Lactobacillus casei thymidylate synthase gene, DNA, 7: 235 (1988).PubMedCrossRefGoogle Scholar
  29. 29.
    R.B. Dunlap, N.G.L. Harding, and F.M. Huennekens, Thymidylate synthetase from aminopterin-resistant Lactobacillus casei Biochemistry 10: 88 (1971).Google Scholar
  30. 30.
    J.D. Hines, D.J. Adelstein, J.L. Spiess, P. Giroski, and S.G. Carter, Efficacy of highdose oral leucovorin and 5-fluorouracil in advanced colorectal carcinoma, Cancer, 63: 1022 (1989).PubMedCrossRefGoogle Scholar
  31. 31.
    L.R. Laufman, W.D. Brenckman, Jr., and K.A. Stydnicki, et al., Clinical experience with leucovorin and 5-fluorouracil, Cancer, 63: 103 (1989).CrossRefGoogle Scholar
  32. 32.
    E.M. Newman, S.A. Akman, and J.S. Harrison, et al., Pharmacokinetics and toxicity of continuous infusion (6S)-folinic acid and bolus 5-fluorouracil in patients with advanced cancer, Cancer Res., 52: 2408 (1992).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • D. G. Priest
    • 1
  • J. C. Schmitz
    • 1
  • T. Walle
    • 2
  1. 1.Department of Biochemistry and Molecular BiologyMedical University of South CarolinaCharlestonUSA
  2. 2.Department of PharmacologyMedical University of South CarolinaCharlestonUSA

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