BIOCHEMICAL MODULATION OF FLUOROPYRIMIDINES - PRECLINICAL AND CLINICAL-STUDIES

The saying 'you can teach an old drug new tricks' has been proven to b e useful in the case of 5-fluorouracil (5-FU), when its ability to be modulated by non-cytotoxic drugs was discovered. This review summarise s experimental preclinical and clinical data on the biochemical modula tion of 5-FU, focusing on the pharmacology of 5-FU and the stereoselec tive pharmacokinetic behaviour of tetrahydrofolates. Several drugs suc h as interferon, N-(phosphonacetyl)-L-aspartate, and methotrexate shar e common modes of action with reduced folates. These substances intera ct mainly with the pyrimidine network responsible for the activation o f 5-FU. Preclinical studies have largely contributed to our understand ing of resistance to modulated 5-FU, e.g. enhanced synthesis of the ta rget enzyme thymidylate synthase. The feasibility of pharmacokinetic i n vivo studies in humans, using new techniques such as nuclear magneti c resonance spectroscopy, enables us to translate preclinical investig ations 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 experimenta l parameters. Thus, individualisation of anti-neoplastic treatment is the main challenge for the coming years.