Inhibition of dihydropyrimidine dehydrogenase by alpha-interferon: experimental data on human tumor cell lines.
Interferons (IFNs) are very promising fluorouracil (FU) biochemical modulators. The pharmacological origin sustaining the FU-IFN synergistic interaction is not clearly understood. It was recently shown that alpha-IFN was associated with a dose-dependent decrease in FU clearance in treated patients. Dihydropyrimidine dehydrogenase (DPD) is the key regulating 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 five human cancer cell lines. All cell lines investigated exhibited quantifiable DPD activity with inter-cell-line variability (0.118-0.318 nmol 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 concentration-dependent significant decrease in DPD activity, reaching 50% of the initial activity determined for the highest IFN concentration (10(5) IU/ml), was demonstrated in all cell lines tested (5-day IFN exposure). For three cell lines, IFN potentiated the FU-induced growth inhibition in a concentration-dependent manner. Considering all cell lines and all IFN concentrations, it appears that globally, the greater the inhibition of DPD activity, the greater the FU potentiation (Spearman rank correlation on all cell lines, P = 0.011).
Milano
G
G
Centre Antoine-Lacassagne, Nice, France.
Fischel
J L
JL
Etienne
M C
MC
Renée
N
N
Formento
P
P
Thyss
A
A
Gaspard
M H
MH
Thill
L
L
Cupissol
D
D
D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology*; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D010088:Oxidoreductases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011994:Recombinant Proteins; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil