Overview: Rational Basis for Development of Fluoropyrimidine/5-Formyltetrahydrofolate Combination Chemotherapy

  • F. M. Huennekens
  • Y. D. Montejano
  • K. S. Vitols
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 244)


Fluorodeoxyuridylate (FdUMP) and thymidylate synthase (TS) are one of the better understood systems of drug-target interaction in cancer chemotherapy. Isolation and characterization of TS (initially from Lactobacillus casei and later from a variety of other sources), cloning and sequencing of the gene, determination of the 3-D structure of the enzyme by X-ray diffraction, and elucidation of the structure of both the catalytic intermediate and the enzyme-inhibitor complex have revealed critical parameters of the target at the molecular level. Potentiation of FdUMP binding by 5,10-methylenetetrahydrofolate (CH2-FH4), discovered at the enzymatic level, has been exploited to increase the clinical effectiveness of fluoropyrimidines. CH2-FH4 can be generated from folate, 5-methyltetrahydrofolate, or 5-formyltetrahydrofolate (citrovorum factor, CF); the latter is the compound of choice for therapeutic regimens. Transformation of CF to CH2-FH4 can occur via two pathways: (a) CF → 5,10-methenyltetrahydrofolate → CH2-FH4; or (b) CF → tetrahydrofolate → CH2-FH4. The relative importance of these pathways in various cells is not yet clear. The role of CH2-FH4 in FdUMP toxicity, and its central position in folate coenzyme-dependent C1 metabolism, emphasize the need for development of methods to quantitate intracellular levels of this compound.


Dihydrofolate Reductase Lactobacillus Casei Serine Hydroxymethyltransferase Scripps Clinic Catalytic Intermediate 
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Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • F. M. Huennekens
    • 1
  • Y. D. Montejano
    • 1
  • K. S. Vitols
    • 1
  1. 1.Division of Biochemistry Department of Basic and Clinical ResearchResearch Institute of Scripps ClinicLa JollaUSA

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