The saying ‘you can teach an old drug new tricks’ has been proven to be useful in the case of 5-fluorouracil (5-FU), when its ability to be modulated by non-cytotoxic drugs was discovered. This review summarises experimental preclinical and clinical data on the biochemical modulation of 5-FU, focusing on the pharmacology of 5-FU and the stereoselective pharmacokinetic behaviour of tetrahydrofolates. Several drugs such as interferon, N-(phosphonacetyl)-L-aspartate, and methotrexate share common modes of action with reduced folates. These substances interact mainly with the pyrimidine network responsible for the activation of 5-FU Preclinical studies have largely contributed to our understanding of resistance to modulated 5-FU, e. g. enhanced synthesis of the target enzyme thymidylate synthase. The feasibility of pharmacokinetic in vivo studies in humans, using new techniques such as nuclear magnetic resonance spectroscopy, enables us to translate preclinical investigations into clinical knowledge. Significant progress in the palliative treatment of colorectal cancer will depend on our ability to predict therapeutic success or therapeutic failure on the basis of experimental parameters. Thus, individualisation of anti-neoplastic treatment is the main challenge for the coming years.

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