NCIt definition : An orally bioavailable inhibitor of both deoxyuridine triphosphatase (dUTPase) and
dihydropyrimidine dehydrogenase (DPD), with potential antineoplastic adjuvant activity.
Upon oral administration in combination with a prodrug of the pyrimidine antagonist
5-fluorouracil (5-FU), TAS-114 inhibits (DPD), the liver enzyme responsible for rapid
catabolism of 5-FU into inactive metabolites. This prevents first-pass metabolism
of 5-FU, allowing oral administration of the 5-FU prodrug and increasing the efficacy
of 5-FU. In addition, as a dUTPase inhibitor, TAS-114 enhances the antitumor activity
of 5-FU by preventing the hydrolysis and breakdown of 5-fluoro-deoxyuridine triphosphate
(FdUTP) and deoxyuridine triphosphate (dUTP), which are active metabolites of 5-FU.
This promotes DNA polymerase-dependent incorporation of these antimetabolites into
DNA and leads to DNA damage and tumor cell death. Co-administration with TAS-114 allows
lower dosing of 5-FU prodrugs, which decreases 5-FU-related toxicity, while maintaining
therapeutic levels of 5-FU at the tumor site.;