Impact of different fluorouracil biochemical modulators on cellular dihydropyrimidine dehydrogenase

Abstract

In attempts to increase fluorouracil (FU) activity by pharmacomodulation, most attention has been paid to FU activation pathways without consideration of the presence and possible role of FU catabolism in the target tumoral cell itself. The first step in the catabolism of FU is hydrogenation by the enzyme dihydropyrimidine dehydrogenase (DPD). The purpose of the present study was to test the DPD-inhibitory effects of several agents whose use as FU biomodulators has been clinically established: cisplatin, hydroxyurea, dipyridamole, and allopurino. Five cancer cell lines of human origin were used. Dipyridamole and hydroxyurea were the only modulators for which an augmentation in FU cell-growth inhibition (MTT test) was clearly evident for the whole panel of cell lines investigated (P<1.10(-4) and P=0.005, respectively). With dipyridamole the efficacy of FU was multiplied by a factor of around 5. Allopurinol and cisplatin had no obvious effect on cellular DPD activity (biochemical method). For dipyridomole and hydroxyurea, DPD activity showed a more or less marked concentration-related inhibition according to the cell line tested. Only dipyridamole produced reductions in FU IC50 values (50% growth-inhibitory concentrations), i.e., potentiation of FU cytotoxicity, that were significantly related to inhibition of cellular DPD activity. This DPD-mediated interaction between dipyridamole and FU is a new finding that could be important for a better understanding of FU-dipyridamole combination chemotherapy.