Enhancement of fluorouracil therapy by the manipulation of tissue uridine pools

Evidence for transport systems that actively concentrate uridine in normal tissues provides a previously unexploited opportunity for manipulation to therapeutic advantage. The ability to expand these pools in a tissue-specific manner by administration of exogenous uridine, inhibition of uridine phosphorylase with BAU or blockade of the facilitated transport of nucleosides with dipyridamole is established. If the apparent defect in the active transport mechanism for uridine in neoplastic cells in culture as well as several model tumors reflect the properties of human neoplasms, a new exploitable therapeutic difference may exist. These approaches may, in the near future, increase the therapeutic effectiveness not only of fluorouracil and the other fluoropyrimidines but also of other agents which disrupt uridine metabolism such as PALA and pyrazofurin.