Wide range for optimal concentration of folinic acid in fluorouracil modulation—Experimental data on human tumour cell lines

Abstract

The clinical use of the fluorouracil (FU)-folinic acid (FA) combination is hampered by the still open choice of the optimal schedule, with marked controversy as concerns the optimal FA dose. This in vitro study on FU-FA combinations in 17 human cancer cell lines, representative of tumour types responding to FU-FA treatment, reassesses the notion of the optimal FA concentration. Cells were exposed for 5 days to various FU-FA concentrations (0.07–77 μM, 14 concentrations, for FU; and 0.0025–100 μM for FA). The growth inhibition was assessed by the MTT test. The investigated cell lines exhibited FU IC 50 ranging from 0.4 to 38.9 μM (median 3.7 μM). In six out of 17 cell lines investigated, the addition of FA did not result in a substantial enhancement of FU cytotoxicity (group 1). For the remaining 11 cell lines responding to FA supplementation (group 2), the maximal enhancement factor ranged from 3 to 8, meaning that in the presence of optimal FA concentration, the efficient FU concentration (IC 50) was reduced by between 3 and 8 as compared to the efficient FU concentration without FA supplementation. For cell lines responding to FA supplementation, the optimal FA concentrations ranged from 10 -7 to 4 × 10 -4M (4000-fold range) with a median value at 9.6 × 10 -7 M. Distribution of cell doubling time was not significantly different between group 1 and group 2. In contrast, the FU ic 50 were significantly different (P = 0.02) between group 1 (median 7.4 μM) and group 2 (median 2.2 μM), thus indicating that cell lines with the greatest FU cytotoxicity enhancement by FA were those intrinsically sensitive to FU and vice versa.