Impact of different fluorouracil biochemical modulators on cellular dihydropyrimidine dehydrogenase

Cancer Chemotherapy and Pharmacology
M C HaazG A Milano

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.,...Continue Reading

Citations

Jun 13, 1998·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·M C EtienneG Milano
Mar 6, 1998·Nature Biotechnology·L H KooleF H van der Veen
Mar 5, 2004·Cancer Cell·Anna D'AngeloMassimo Zollo
Jul 21, 2012·Journal of Economic Entomology·Trevor A LambkinMyron P Zalucki

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