Biochemical pharmacology and analysis of fluoropyrimidines alone and in combination with modulators

After more than three decades since their introduction, fluoropyrimidines, especially FUra, are still a mainstay in the treatment of various solid malignancies. The antitumor effects of fluoropyrimidines are dependent upon metabolic activation. FdUMP, FUTP and FdUTP were identified as the key cytotoxic metabolites that interfere with the proper function of thymidylate synthase and nucleic acids. The relevance of these metabolites is cell-type specific. Recently, fluorouridine diphospho sugars have been detected, but the precise function of this class of metabolites is currently unknown. In mammalian systems fluoropyrimidines and their natural counterparts share the same metabolic pathways since the substrate properties in enzyme-catalyzed reactions are frequently comparable. Ongoing studies indicate that the metabolism and action of fluoropyrimidines exhibit circadian rhythms, which appear to be due to variations in the activity of metabolizing enzymes. Essential for the expanding knowledge of the pathways and effects of fluoropyrimidines has been the constant improvement of analytical methods. These include ligand binding techniques, numerous dedicated HPLC systems and 19F-NMR. Because the overall response rates achieved with fluoropyrimidines are modest, strategies based on biochemical modulation have been devised to enhance their therapeutic index. Biochemical modulators include a wide range of various compounds with different modes of action. In recently completed clinical trials, combinations of FUra with leucovorin, a precursor for 5,10-methylene tetrahydrofolate, or with levamisole, an anthelminthic with immunomodulatory activity, appeared to be superior to FUra alone. At the preclinical level combinations of fluoropyrimidines with, e.g. interferons or L-histidinol were demonstrated to be interesting candidates for further testing. The future therapeutic utility of fluoropyrimidines will depend on both the improvement of combination regimens currently used in the treatment of cancer patients and the judicious clinical implementation of promising experimental modulation strategies. Moreover, novel fluoropyrimidines with superior pharmacological properties may become important as part of or instead of modulation approaches.