Skip to main content
SpringerLink
Log in

5-Fluorouracil Combined with the Pure [6S]-Stereoisomer of Folinic Acid in High Doses for Treatment of Patients with Advanced Colorectal Carcinoma: A Phase I–II Study of two Consecutive Regimens

  • Chapter
Novel Approaches to Selective Treatments of Human Solid Tumors

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 339))

Abstract

Folinic acid ([6R,S]-5-CHO-FH4) given in concentrations greatly exceeding that required for optimal cell growth, increases the cytotoxic action of 5-fluorouracil (5-FU) and fluorodeoxyuridine (FUdR)] in vitro (1,2,3). Potentiation of the antitumor activity of 5-FU by folinic acid has been demonstrated in patients with gastrointestinal carcinomas (4–10); this has resulted in effective palliative treatment for patients with advanced colorectal adenocarcinoma (607).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ullman B, Lee M, Martin Dw Jr, et al: Cytotoxicity of 5-fluoro-2′-deoxyuridine: Requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA 75: 980–983, 1978

    Article  PubMed  CAS  Google Scholar 

  2. Keyomarsi K, Moran R: Mechanism of the cytotoxic synergism of fluoropyrimidines and folinic acid in mouse leukemic cells. J Biol Chem 263: 14402–14409, 1988

    PubMed  CAS  Google Scholar 

  3. Piedbois P, Buyse M, Rustum Y, et al, for the Advanced Colorectal Cancer Meta-Analysis Project: Modulation of 5-fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10: 896–903, 1992

    Google Scholar 

  4. Machover D, Schwarzenberg L, Goldschmidt E, et al: Treatment of advanced colorectal and gastric carcinomas with 5-FU combined with high-dose folinic acid: A pilot study. Cancer Treat Rep 66: 1803–1807, 1982

    PubMed  CAS  Google Scholar 

  5. Arbuck S: Overview of clinical trials using 5-fluorouracil and leucovorin for the treatment of colorectal cancer. Cancer 63: 1036–1044, 1989

    Article  PubMed  CAS  Google Scholar 

  6. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6: 469–475, 1988

    PubMed  CAS  Google Scholar 

  7. Poon Ma, O’Connell Mj, Moertel Cg, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7: 1407–1417, 1989

    PubMed  CAS  Google Scholar 

  8. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5: 1559–1565, 1987

    PubMed  CAS  Google Scholar 

  9. Petrelli N, Douglass Ho, Jr, Herrera L, et al: The modulation of 5-fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial. J Clin Oncol 7: 1419–1426, 1989

    PubMed  CAS  Google Scholar 

  10. Doroshow Jh, Multhauf P, Leong L, et al: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8: 491–501, 1990

    PubMed  CAS  Google Scholar 

  11. Levans RM, Laskin JD, Hakala MT: Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 41: 3288–3295, 1981

    Google Scholar 

  12. Swain SM, Lippman ME, Egan EF, et al: Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 7: 890–899, 1989

    PubMed  CAS  Google Scholar 

  13. Lockshin A, Danenberg Pv: Biochemical factors affecting the tightness of 5-ftuorodeoxyuridylate binding to human thymidylate synthetase. Biochem Pharmacol 30: 247–257, 1981

    Article  PubMed  CAS  Google Scholar 

  14. Houghton JA, Williams LG, Cheshire PJ, et al: Influence of dose of [6RS] leucovorin on reduced folate pools and 5-fluorouracil-mediated thymidylate synthase inhibition in human colon adenocarcinoma xenografts. Cancer Res 50: 3940–3946, 1990

    PubMed  Google Scholar 

  15. Machover D: Potentiation of the antitumor activity of the fluoropyrimidines by leucovorin: Rationale and clinical data. In: Pinedo HM, Rustum YM, eds. Leucovorin modulation of fluoropyrimidines: A new frontier in cancer chemotherapy. International congress and symposium series number 158. London — New York: Royal Society of Medicine Services, 1989: 1–9

    Google Scholar 

  16. Valone Fh, Friedman Ma, Wittlinger Ps, et al: Treatment of patients with advanced colorectal carcinomas with 5-fluorouracil alone, high-dose leucovorin plus 5-fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol 7: 1427–1436, 1989

    PubMed  CAS  Google Scholar 

  17. White JC, Bailey BD, Goldman ID: Lack of stereospecificity at carbon 6 of methyltetrahydrofoiate transport in Ehrlich ascites tumor cells. Carrier-mediated transport of both stereoisomers. J Biol Chem 253: 242–245, 1978

    PubMed  CAS  Google Scholar 

  18. Sirotnak FM, Chello PL, Moccio DM, et al: Stereospecificity at carbon 6 of formyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexate in vitro. Biochem Pharmacol 28: 2993–2997, 1979

    Article  PubMed  CAS  Google Scholar 

  19. 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 81: 1175–1178, 1989

    Article  PubMed  CAS  Google Scholar 

  20. Sato JK, Moran RG: Interaction of methotrexate and citrovorum factor at folyl polyglutamate synthetase. Proc Am Assoc Cancer Res 3: 312, 1984 (abstr)

    Google Scholar 

  21. Romanini A, Lin Jt, Niedzwiecki D, et al: Role of polyglutamates in biochemical modulation of fluoropyrimidines by leucovorin. Cancer Res 51: 789–793, 1991

    PubMed  CAS  Google Scholar 

  22. Radvadpar S, Houghton PJ, Houghton JA: Effect of poiyglutamylation of 5, 10-methylenetetrahydrofolate on the binding of 5-fluoro-2′-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft. Biochem Pharmacol 38: 335–342, 1989

    Article  Google Scholar 

  23. Machover D, Goldschmidt E, Chollet P, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4: 685–696, 1986

    PubMed  CAS  Google Scholar 

  24. Newman EM, Straw JA, Doroshow JH: Pharmacokinetics of diastereoisomers of [6R,S]-folinic acid (leucovorin) in humans during constant high-dose intravenous infusion. Cancer Res 49: 5755–5760, 1989.

    PubMed  CAS  Google Scholar 

  25. Zhang Zg, Rustum Ym: Effects of diastereoisomers of 5-formyltetrahydrofolate on cellular growth, sensitivity to 5-fluoro-2′-deoxyuridine, and methylenetetrahydrofolate polygliitamate levels in HCT-8 cells. Cancer Res 51: 3476–3481, 1991

    PubMed  CAS  Google Scholar 

  26. Mcguire Jj, Russell Ca. Biological and biochemical properties of the natural (6S) and the unnatural (6R) isomers of leucovorin and their racemic (6R,S) mixture. J Cell Pharmacol 2: 317–323, 1991

    Google Scholar 

  27. Machover D, Grison X, Goldschmidt E et al. 5-Fluorouracil combined with the pure [6S]-stereoisomer of folinic acid in high doses for treatment of patients with advanced colorectal carcinoma. A phase I-II study. J Natl Cancer Inst 84: 321–327, 1992

    Article  PubMed  CAS  Google Scholar 

  28. Who Handbook for reporting results of cancer treatment. Geneva, World Health Organization, 1979

    Google Scholar 

  29. Moran Rg, Scanlon Kl: Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Res 51: 4618–4623, 1991

    PubMed  CAS  Google Scholar 

  30. Wright JE, Dreyfuss A, El-Magharbel I, et al: Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo. Cancer Res 49: 2592–2596, 1989

    PubMed  CAS  Google Scholar 

  31. Houghton JA, Williams LG,, de Graaf SSN et al: Relationship between dose rate of [6RS]-leucovorin administration, plasma concentrations of reduced folates, and pools of 5, 10-methylene tetrahydrofolates and tetrahydrotblates in human adenocarcinoma xenografts. Cancer Res 50: 3493–3502, 1990

    PubMed  CAS  Google Scholar 

  32. Lokich JJ, Ahlgren JD, Gullo JJ, et al: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology Program study. J Clin Oncol 7: 425–432, 1989

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Hospital Tenon, Paris, France

    David Machover, Xavier Grison, Jean-Pierre Lotz, Serge Mauban & Victor Izrael

  2. Service of Hematology and Oncology, Hospital Paul Brousse, Villejuif, France

    Emma Goldschmidt & Gerard Metzger

  3. Service of Hematology and Immunology, Hospital Henri Mondor, Créteil, France

    Jacqueline Zittoun & Jeanine Marquet

  4. Service of Radiology, Hospital Tenon, Paris, France

    Jocelyne Richaud

  5. Service of Surgery, Hospital Saint Antoine, Paris, France

    Laurent Hannoun

  6. Lederle Laboratories, Rungis, France

    Thierry Guillot, Mia Bardon & Rolland Parc

  7. Service of Surgery, Institut Curie, Paris, France

    Rémy Salmon

  8. Service of Surgery, Hospital Rothschild, Paris, France

    Alain Sezeur

Authors
  1. David Machover
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xavier Grison
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emma Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacqueline Zittoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Pierre Lotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gerard Metzger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jocelyne Richaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laurent Hannoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeanine Marquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thierry Guillot
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mia Bardon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rémy Salmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alain Sezeur
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Serge Mauban
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rolland Parc
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Victor Izrael
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York, USA

    Youcef M. Rustum

Rights and permissions

Reprints and permissions

Copyright information

© 1993 Springer Science+Business Media New York

About this chapter

Cite this chapter

Machover, D. et al. (1993). 5-Fluorouracil Combined with the Pure [6S]-Stereoisomer of Folinic Acid in High Doses for Treatment of Patients with Advanced Colorectal Carcinoma: A Phase I–II Study of two Consecutive Regimens. 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_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-2488-5_10

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6060-5

  • Online ISBN: 978-1-4615-2488-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation