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Chemical Compound Review

leucovorin     (2S)-2-[[4-[(2-amino-5- methanoyl-4-oxo-1,6...

Synonyms: folinate, Leucal, Leucoverin, Welcovorin, Leucovorinum, ...
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Disease relevance of leucovorin


High impact information on leucovorin


Chemical compound and disease context of leucovorin


Biological context of leucovorin


Anatomical context of leucovorin

  • Although leucovorin had been shown to selectively spare normal bone marrow and intestine in animals from the killing effect of MTX on tumor cells, we demonstrate the preferential killing of neoplastic over non-neoplastic cells of the same derivation [21].
  • This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity [22].
  • Our results indicate that, in HDMTX-treated mice, leucovorin protection involves the earliest stages of hemopoiesis, assuring the maintenance of a satisfactory endowment of stem and progenitor cells [23].
  • After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol [24].
  • However, the effect of leucovorin on peripheral blood cell reduction was less significant [23].

Associations of leucovorin with other chemical compounds


Gene context of leucovorin

  • Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation [30].
  • We have demonstrated previously that interferon (IFN)-gamma sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53 [31].
  • MTX, FA, and leucovorin are subject to high capacity [V(max(MTX)), 0.24 +/- 0.05 nmol/mg/min; V(max (FA)), 0.68 +/- 0.14 nmol/mg/min; V(max(leucovorin)), 1.95 +/- 0.18 nmol/mg/min], low affinity [K(m(MTX)), 0.22 +/- 0.01 mM; K(m(FA)), 0.17 +/- 0.02 mM; K(m (leucovorin)), 0.64 +/- 0.23 mM] transport by MRP4 [32].
  • Replenishment of LCV in the growth medium of CEM-7A cells resulted in resumption of normal MRP1 expression [33].
  • CONCLUSIONS: We were unable to demonstrate a survival difference between those stage III colon cancer patients receiving leucovorin therapy that carried the MTHFR C677T allele and those that were wild type for this allele [34].

Analytical, diagnostic and therapeutic context of leucovorin


  1. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. Ledermann, J.A., Leonard, P., Seymour, M. N. Engl. J. Med. (2001) [Pubmed]
  2. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. Stoller, R.G., Hande, K.R., Jacobs, S.A., Rosenberg, S.A., Chabner, B.A. N. Engl. J. Med. (1977) [Pubmed]
  3. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. Fisher, B., Redmond, C., Dimitrov, N.V., Bowman, D., Legault-Poisson, S., Wickerham, D.L., Wolmark, N., Fisher, E.R., Margolese, R., Sutherland, C. N. Engl. J. Med. (1989) [Pubmed]
  4. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. Kemeny, N., Huang, Y., Cohen, A.M., Shi, W., Conti, J.A., Brennan, M.F., Bertino, J.R., Turnbull, A.D., Sullivan, D., Stockman, J., Blumgart, L.H., Fong, Y. N. Engl. J. Med. (1999) [Pubmed]
  5. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. Evans, W.E., Crom, W.R., Abromowitch, M., Dodge, R., Look, A.T., Bowman, W.P., George, S.L., Pui, C.H. N. Engl. J. Med. (1986) [Pubmed]
  6. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. Macdonald, J.S., Smalley, S.R., Benedetti, J., Hundahl, S.A., Estes, N.C., Stemmermann, G.N., Haller, D.G., Ajani, J.A., Gunderson, L.L., Jessup, J.M., Martenson, J.A. N. Engl. J. Med. (2001) [Pubmed]
  7. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. Wolmark, N., Wieand, H.S., Hyams, D.M., Colangelo, L., Dimitrov, N.V., Romond, E.H., Wexler, M., Prager, D., Cruz, A.B., Gordon, P.H., Petrelli, N.J., Deutsch, M., Mamounas, E., Wickerham, D.L., Fisher, E.R., Rockette, H., Fisher, B. J. Natl. Cancer Inst. (2000) [Pubmed]
  8. Overview of combined modality therapies for head and neck cancer. Dimery, I.W., Hong, W.K. J. Natl. Cancer Inst. (1993) [Pubmed]
  9. Phase I study of (6R)-5,10-dideazatetrahydrofolate: a folate antimetabolite inhibitory to de novo purine synthesis. Ray, M.S., Muggia, F.M., Leichman, C.G., Grunberg, S.M., Nelson, R.L., Dyke, R.W., Moran, R.G. J. Natl. Cancer Inst. (1993) [Pubmed]
  10. Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer. Vokes, E.E., Weichselbaum, R.R., Mick, R., McEvilly, J.M., Haraf, D.J., Panje, W.R. J. Natl. Cancer Inst. (1992) [Pubmed]
  11. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Pestalozzi, B.C. N. Engl. J. Med. (2001) [Pubmed]
  12. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Lévi, F.A., Zidani, R., Vannetzel, J.M., Perpoint, B., Focan, C., Faggiuolo, R., Chollet, P., Garufi, C., Itzhaki, M., Dogliotti, L. J. Natl. Cancer Inst. (1994) [Pubmed]
  13. Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate. Allegra, C.J., Kovacs, J.A., Drake, J.C., Swan, J.C., Chabner, B.A., Masur, H. J. Clin. Invest. (1987) [Pubmed]
  14. Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines. Park, J.G., Collins, J.M., Gazdar, A.F., Allegra, C.J., Steinberg, S.M., Greene, R.F., Kramer, B.S. J. Natl. Cancer Inst. (1988) [Pubmed]
  15. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. Van Cutsem, E., Findlay, M., Osterwalder, B., Kocha, W., Dalley, D., Pazdur, R., Cassidy, J., Dirix, L., Twelves, C., Allman, D., Seitz, J.F., Schölmerich, J., Burger, H.U., Verweij, J. J. Clin. Oncol. (2000) [Pubmed]
  16. Failure of high-dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance? Martin, D.S., Stolfi, R.L., Colofiore, J.R. J. Natl. Cancer Inst. (1988) [Pubmed]
  17. Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously. Priest, D.G., Schmitz, J.C., Bunni, M.A., Stuart, R.K. J. Natl. Cancer Inst. (1991) [Pubmed]
  18. Thymineless death in colon carcinoma cells is mediated via fas signaling. Houghton, J.A., Harwood, F.G., Tillman, D.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  19. Antifolate polyglutamylation and competitive drug displacement at dihydrofolate reductase as important elements in leucovorin rescue in L1210 cells. Matherly, L.H., Barlowe, C.K., Goldman, I.D. Cancer Res. (1986) [Pubmed]
  20. Cytokinetic comparison of thymidine and leucovorin rescue of marrow in humans after exposure to high-dose methotrexate. Howell, S.B., Krishan, A., Frei, E. Cancer Res. (1979) [Pubmed]
  21. Selective killing of preneoplastic and neoplastic cells by methotrexate with leucovorin. Chow, M., Rubin, H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  22. Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. Crown, J., Casper, E.S., Botet, J., Murray, P., Kelsen, D.P. J. Clin. Oncol. (1991) [Pubmed]
  23. Effects of high-dose methotrexate and leucovorin on murine hemopoietic stem cells. Pannacciulli, I., Massa, G., Bogliolo, G., Ghio, R., Sobrero, A. Cancer Res. (1982) [Pubmed]
  24. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. Ducreux, M., Ychou, M., Laplanche, A., Gamelin, E., Lasser, P., Husseini, F., Quenet, F., Viret, F., Jacob, J.H., Boige, V., Elias, D., Delperro, J.R., Luboinski, M. J. Clin. Oncol. (2005) [Pubmed]
  25. Phase I/II study of cyclophosphamide, doxorubicin, fluorouracil, and leucovorin for treatment of metastatic adenocarcinoma. Parnes, H.L., Abrams, J.S., Tait, N., Minford, J., Allen, S.L., Duggan, D., Aisner, J. J. Natl. Cancer Inst. (1991) [Pubmed]
  26. The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides. Pinedo, H.M., Zaharko, D.S., Bull, J.M., Chabner, B.A. Cancer Res. (1976) [Pubmed]
  27. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. Lenz, H.J., Leichman, C.G., Danenberg, K.D., Danenberg, P.V., Groshen, S., Cohen, H., Laine, L., Crookes, P., Silberman, H., Baranda, J., Garcia, Y., Li, J., Leichman, L. J. Clin. Oncol. (1996) [Pubmed]
  28. Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium. Levin, R.D., Gordon, J.H., Simonich, W., Mellijor, A., Sanchez, R., Williams, R.M. J. Clin. Oncol. (1991) [Pubmed]
  29. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. Swain, S.M., Lippman, M.E., Egan, E.F., Drake, J.C., Steinberg, S.M., Allegra, C.J. J. Clin. Oncol. (1989) [Pubmed]
  30. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. Rustum, Y.M., Harstrick, A., Cao, S., Vanhoefer, U., Yin, M.B., Wilke, H., Seeber, S. J. Clin. Oncol. (1997) [Pubmed]
  31. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells. Geller, J.I., Szekely-Szucs, K., Petak, I., Doyle, B., Houghton, J.A. Cancer Res. (2004) [Pubmed]
  32. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Chen, Z.S., Lee, K., Walther, S., Raftogianis, R.B., Kuwano, M., Zeng, H., Kruh, G.D. Cancer Res. (2002) [Pubmed]
  33. Loss of multidrug resistance protein 1 expression and folate efflux activity results in a highly concentrative folate transport in human leukemia cells. Assaraf, Y.G., Rothem, L., Hooijberg, J.H., Stark, M., Ifergan, I., Kathmann, I., Dijkmans, B.A., Peters, G.J., Jansen, G. J. Biol. Chem. (2003) [Pubmed]
  34. MTHFR (C677T) polymorphisms and stage III colon cancer: response to therapy. Wisotzkey, J.D., Toman, J., Bell, T., Monk, J.S., Jones, D. Mol. Diagn. (1999) [Pubmed]
  35. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. Saltz, L.B., Cox, J.V., Blanke, C., Rosen, L.S., Fehrenbacher, L., Moore, M.J., Maroun, J.A., Ackland, S.P., Locker, P.K., Pirotta, N., Elfring, G.L., Miller, L.L. N. Engl. J. Med. (2000) [Pubmed]
  36. Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. Schilsky, R.L., Ratain, M.J. J. Natl. Cancer Inst. (1990) [Pubmed]
  37. Prolonged continuous infusion of fluorouracil with weekly bolus leucovorin: a phase II study in patients with disseminated colorectal cancer. Leichman, C.G., Leichman, L., Spears, C.P., Rosen, P.J., Jeffers, S., Groshen, S. J. Natl. Cancer Inst. (1993) [Pubmed]
  38. Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. Porschen, R., Bermann, A., Löffler, T., Haack, G., Rettig, K., Anger, Y., Strohmeyer, G. J. Clin. Oncol. (2001) [Pubmed]
  39. Pharmacokinetics of diastereoisomers of (6R,S)-folinic acid (leucovorin) in humans during constant high-dose intravenous infusion. Newman, E.M., Straw, J.A., Doroshow, J.H. Cancer Res. (1989) [Pubmed]
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