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Biochemical Bases of the 5-Fluorouracil—Folinic Acid Interaction and of its Limitations

A Retrospective Analysis

  • Chapter
Fluoropyrimidines in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Summary

The sensitivity of many, but not all, human carcinoma cell lines to 5-fluorouracil (5-FU) is substantially increased by exposure of cells to 0.3–10 µM concentrations of reduced folates. The synergism is due to an enhanced kinetic trapping of thymidylate synthase (TS) in an inactive ternary complex, which, although covalent, is in dynamic equilibrium with unbound, active enzyme. Several factors interact to prevent or reverse complete inhibition of TS by fluoropyrimidines. Yet, cellular TS must be maintained completely inactive for a length of time equivalent to one cell generation before any appreciable cell kill ensues. Successful blockade for longer periods yields extensive commitment to cell death, and antitumor kill has been faithfully mirrored by the duration of complete inhibition of TS in those few studies that allow assessment of the time course of enzyme inhibition. In spite of the potency of 5-FU as an inhibitor of TS, maintenance of such a prolonged complete blockade of tumor TS is quite difficult under clinical conditions. These counterintuitive concepts are borne out by abundant preclinical information, and may lie behind the limited clinical activity of the drug. However, the current literature would support the conclusions that the therapeutic objective of fluoropyrimidine therapy is a sustained complete inhibition of TS for periods of 48 h or more, that such inhibition should permit substantial therapeutic effects against human colon carcinomas, and that this objective is probably seldom met.

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Authors
  1. Richard G. Moran PhD
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Editors and Affiliations

  1. Roswell Park Cancer Institute, Buffalo, NY, USA

    Youcef M. Rustum

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© 2003 Springer Science+Business Media New York

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Moran, R.G. (2003). Biochemical Bases of the 5-Fluorouracil—Folinic Acid Interaction and of its Limitations. In: Rustum, Y.M. (eds) Fluoropyrimidines in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-337-8_3

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  • DOI: https://doi.org/10.1007/978-1-59259-337-8_3

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-274-2

  • Online ISBN: 978-1-59259-337-8

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