Dual modulation of 5-fluorouracil cytotoxicity using folinic acid with a dihydropyrimidine dehydrogenase inhibitor.

Dihydropyrimidine dehydrogenase (DPD) is the key enzyme of the fluorouracil (FU) catabolic pathway. We have shown that tumor cells expressing a high DPD activity are resistant to FU (Eur J Cancer 30: 1517, 1994), and that 5-ethynyluracil (776C), a very potent DPD inactivator, markedly enhances the FU cytotoxic effect (Clin Cancer Res 1: 991, 1995). Both experimental background and clinical experience have demonstrated the role of folinic acid (FA) in increasing FU efficacy. The aim of the present study was to investigate the dual FU pharmacomodulation based on the combination of FU with 776C and/or FA on 7 human cancer cell lines (2 head and neck, 3 breast, 1 colon, 1 duodenum) expressing a spontaneous FU sensitivity. These cell lines were chosen according to their ability to respond to FU modulation by FA and/or 776C. The potency of FU modulation was evaluated by the ratio between FU IC50 and FU IC50 in the presence of the tested biomodulator(s), defined as factor F. In cell lines sensitive to FU modulation by 776C only (median F value with 1 microM of 776C = 2.5), the addition of FA did not enhance FU-776C cytotoxicity. In contrast, for cell lines resistant to FU modulation by 776C, the FU-FA-776C combination led to a significant cytotoxicity enhancement as compared to FU-FA (median F values were 3.6 and 2.6 respectively). In cell lines responsive to FU modulation by FA and 776C, the median F values were 2.3 and 1.8 with FA and 776C, respectively. Interestingly, the dual modulation by FA + 776C led to a median F value at 6.3, suggesting more than the additive effects of FA and 776C. This synergistic interaction was statistically confirmed by multivariate ANOVA (FA x 776C interaction). The present study points out that FA plus 776C could prove to be a very attractive combination for future strategies in FU biomodulation.