INHIBITION OF DIHYDROPYRIMIDINE DEHYDROGENASE BY ALPHA-INTERFERON - EXPERIMENTAL-DATA ON HUMAN TUMOR-CELL LINES

Interferons (IFNs) are very promising fluorouracil (FU) biochemical mo dulators. The pharmacological origin sustaining the FU-IFN synergistic interaction is not clearly understood. It was recently shown that a-I FN was associated with a dose-dependent decrease in FU clearance in tr eated patients. Dihydropyrimidine dehydrogenase (DPD) is the key regul ating enzyme for FU catabolism. The effects on DPD exerted by both the IFN dose and the duration of exposure were evaluated in a panel of fi ve human cancer cell lines. All cell lines investigated exhibited quan tifiable DPD activity with inter-cell-line variability (0.118-0.318 nm ol min(-1) mg protein(-1)). A prolonged exposure to IFN (up to 5 days) was necessary to obtain a significant inhibition of DPD activity. A c oncentration-dependent significant decrease in DPD activity, reaching 50% of the initial activity determined for the highest IFN concentrati on (10(5) IU/ml), was demonstrated in all cell lines tested (5-day IFN exposure). For three cell lines, IFN potentiated the FU-induced growt h inhibition in a concentration-dependent manner. Considering all cell lines and all IFN concentrations, it appears that globally, the great er the inhibition of DPD activity, the greater the FU potentiation (Sp earman rank correlation on all cell lines, P = 0.011).