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

Summary

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.

This is publication 5359-BCR from the Research Institute of Scripps Clinic. Experimental work was supported by Grant CA-39836 (Outstanding Investigator Award) from the National Cancer Institute and Grant CH-31 from the American Cancer Society.