Consensus interferon enhances the anti-proliferative effect of 5-fluorouracil on human hepatoma cells via downregulation of dihydropyrimidine dehydrogenase expression.
OBJECTIVE
The effectiveness of 5-fluorouracil (5-FU) treatment is influenced by the activities of pyrimidine catabolic enzymes. The aim of this study was to investigate whether interferon (IFN)-alpha influences expression of 5-FU catabolic or target-related enzymes in human hepatoma cells.


METHODS
HepG2 cells were treated with 0, 0.15, 1.5, 15, and 150 ng/ml of consensus interferon (C-IFN). Expression of mRNAs encoding dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase, and thymidylate synthase was examined by reverse transcription-polymerase chain reaction before and after C-IFN treatment. To determine the effect of pretreatment with C-IFN on 5-FU+C-IFN combination therapy, we performed WST-1 cell proliferation assays.


RESULTS
A significant reduction in the level of DPD mRNA was observed when HepG2 cells were pretreated with C-IFN (P<0.05). This reduction occurred in a time-dependent manner. Cell proliferation was reduced most significantly when HepG2 cells were treated with 5-FU and C-IFN. Furthermore, when cells were pretreated with C-IFN for 3 days, the anti-proliferative effect of 5-FU+C-IFN combination therapy was augmented significantly (P<0.05).


CONCLUSIONS
C-IFN likely improves the anti-tumor effect of 5-FU via downregulation of DPD enzyme in hepatoma cells. Pretreatment with C-IFN may increase the anti-cancer effect of 5-FU+C-IFN combination therapy.
Dou
Jian
J
Department of Surgery I, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
Iwashita
Yukio
Y
Sasaki
Atsushi
A
Kai
Seiichiro
S
Hirano
Seitaro
S
Ohta
Masayuki
M
Kitano
Seigo
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004338:Drug Combinations; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D004338:Drug Combinations; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; C050739:interferon alfacon-1; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil