Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1991 Jun;63(6):885–888. doi: 10.1038/bjc.1991.194

Comparative effect of 6S, 6R and 6RS leucovorin on methotrexate rescue and on modulation of 5-fluorouracil.

J Zittoun 1, J Marquet 1, J J Pilorget 1, C Tonetti 1, E De Gialluly 1
PMCID: PMC1972534  PMID: 2069845

Abstract

The comparative efficacy of the pure diastereoisomers of leucovorin, the natural (6S) and the unnatural (6R) forms was compared to the racemic form (6RS). A protective effect in methotrexate-treated CCRF-CEM cells was obtained with 6S at concentrations 100-fold higher than those of methotrexate and with 6RS at concentrations 2-fold greater than those of 6S; however, at low concentrations of methotrexate, 6S was more effective than 6RS in preventing the cytotoxicity of methotrexate; on the opposite, 6R exhibited a protective effect at concentrations 10(4) higher than those of methotrexate. On the same cell line, 6S was shown to enhance the cytotoxic effect of 5 Fluorouracil exactly as 6RS while 6R did not exhibit any enhancing effect on cells exposed to 5 Fluorouracil.

Full text

PDF
885

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bertrand R., Jolivet J. Lack of interference by the unnatural isomer of 5-formyltetrahydrofolate with the effects of the natural isomer in leucovorin preparations. J Natl Cancer Inst. 1989 Aug 2;81(15):1175–1178. doi: 10.1093/jnci/81.15.1175. [DOI] [PubMed] [Google Scholar]
  2. Bertrand R., Jolivet J. The natural and unnatural diastereomers of leucovorin: aspects of their cellular pharmacology. Adv Exp Med Biol. 1988;244:13–24. doi: 10.1007/978-1-4684-5607-3_2. [DOI] [PubMed] [Google Scholar]
  3. Dluzewski A. R., Rangachari K., Wilson R. J., Gratzer W. B. Entry of malaria parasites into resealed ghosts of human and simian erythrocytes. Br J Haematol. 1981 Sep;49(1):97–101. doi: 10.1111/j.1365-2141.1981.tb07201.x. [DOI] [PubMed] [Google Scholar]
  4. Evans R. M., Laskin J. D., Hakala M. T. Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res. 1981 Sep;41(9 Pt 1):3288–3295. [PubMed] [Google Scholar]
  5. Huennekens F. M., Duffy T. H., Vitols K. S. Folic acid metabolism and its disruption by pharmacologic agents. NCI Monogr. 1987;(5):1–8. [PubMed] [Google Scholar]
  6. KILLMANN S. A. EFFECT OF DEOXYURIDINE ON INCORPORATION OF TRITIATED THYMIDINE: DIFFERENCE BETWEEN NORMOBLASTS AND MEGALOBLASTS. Acta Med Scand. 1964 Apr;175:483–488. doi: 10.1111/j.0954-6820.1964.tb00597.x. [DOI] [PubMed] [Google Scholar]
  7. Keyomarsi K., Moran R. G. Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res. 1986 Oct;46(10):5229–5235. [PubMed] [Google Scholar]
  8. Lee P. P., Schilsky R. L. Inhibition of thymidylate synthase by the diastereoisomers of leucovorin. Cancer Chemother Pharmacol. 1990;26(4):273–277. doi: 10.1007/BF02897229. [DOI] [PubMed] [Google Scholar]
  9. Machover D., Goldschmidt E., Chollet P., Metzger G., Zittoun J., Marquet J., Vandenbulcke J. M., Misset J. L., Schwarzenberg L., Fourtillan J. B. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol. 1986 May;4(5):685–696. doi: 10.1200/JCO.1986.4.5.685. [DOI] [PubMed] [Google Scholar]
  10. Matherly L. H., Czajkowski C. A., Muench S. P., Psiakis J. T. Role for cytosolic folate-binding proteins in the compartmentation of endogenous tetrahydrofolates and the 5-formyl tetrahydrofolate-mediated enhancement of 5-fluoro-2'-deoxyuridine antitumor activity in vitro. Cancer Res. 1990 Jun 1;50(11):3262–3269. [PubMed] [Google Scholar]
  11. McGuire J. J., Hsieh P., Coward J. K., Bertino J. R. Enzymatic synthesis of folylpolyglutamates. Characterization of the reaction and its products. J Biol Chem. 1980 Jun 25;255(12):5776–5788. [PubMed] [Google Scholar]
  12. Metz J., Kelly A., Swett V. C., Waxman S., Herbert V. Deranged DNA synthesis by bone marrow from vitamin B-12-deficient humans. Br J Haematol. 1968 Jun;14(6):575–592. doi: 10.1111/j.1365-2141.1968.tb00364.x. [DOI] [PubMed] [Google Scholar]
  13. Metz J. The deoxyuridine suppression test. Crit Rev Clin Lab Sci. 1984;20(3):205–241. doi: 10.3109/10408368409165775. [DOI] [PubMed] [Google Scholar]
  14. Mini E., Moroson B. A., Bertino J. R. Cytotoxicity of floxuridine and 5-fluorouracil in human T-lymphoblast leukemia cells: enhancement by leucovorin. Cancer Treat Rep. 1987 Apr;71(4):381–389. [PubMed] [Google Scholar]
  15. Rustum Y. M., Trave F., Zakrzewski S. F., Petrelli N., Herrera L., Mittelman A., Arbuck S. G., Creaven P. J. Biochemical and pharmacologic basis for potentiation of 5-fluorouracil action by leucovorin. NCI Monogr. 1987;(5):165–170. [PubMed] [Google Scholar]
  16. Schilsky R. L., Ratain M. J. Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Natl Cancer Inst. 1990 Sep 5;82(17):1411–1415. doi: 10.1093/jnci/82.17.1411. [DOI] [PubMed] [Google Scholar]
  17. Sirotnak F. M., Chello P. L., Moccio D. M., Kisliuk R. L., Combepine G., Gaumont Y., Montgomery J. A. Stereospecificity at carbon 6 of fomyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexate in vitro. Biochem Pharmacol. 1979 Oct 1;28(19):2993–2997. doi: 10.1016/0006-2952(79)90599-9. [DOI] [PubMed] [Google Scholar]
  18. Straw J. A., Newman E. M., Doroshow J. H. Pharmacokinetics of leucovorin (D,L-5-formyltetrahydrofolate) after intravenous injection and constant intravenous infusion. NCI Monogr. 1987;(5):41–45. [PubMed] [Google Scholar]
  19. Ullman B., Lee M., Martin D. W., Jr, Santi D. V. Cytotoxicity of 5-fluoro-2'-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci U S A. 1978 Feb;75(2):980–983. doi: 10.1073/pnas.75.2.980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Yin M. B., Zakrzewski S. F., Hakala M. T. Relationship of cellular folate cofactor pools to the activity of 5-fluorouracil. Mol Pharmacol. 1983 Jan;23(1):190–197. [PubMed] [Google Scholar]
  21. Zittoun J., Marquet J., Zittoun R. Effect of folate and cobalamin compounds on the deoxyuridine suppression test in vitamin B12 and folate deficiency. Blood. 1978 Jan;51(1):119–128. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES