Alteration of dihydropyrimidine dehydrogenase expression by IFN-alpha affects the antiproliferative effects of 5-fluorouracil in human hepatocellular carcinoma cells.
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) and its activity is closely associated with cellular sensitivity to 5-FU. This study examines the role of DPD in the antiproliferative effects of 5-FU combined with IFN-alpha on hepatocellular carcinoma (HCC) cells in culture and asks whether IFN-alpha could affect DPD expression. The combined action of IFN-alpha and 5-FU on three HCC lines was quantified by a combination index method. Coadministration of IFN-alpha and 5-FU showed synergistic effects against HAK-1A and KYN-2 but antagonistic effects against KYN-3. The cellular expression levels of DPD mRNA and protein were markedly up-regulated in KYN-3 cells by IFN-alpha but were down-regulated in HAK-1A and KYN-2. The expression of thymidylate synthase mRNA and protein was down-regulated by IFN-alpha in all three cell lines. Coadministration of a selective DPD inhibitor, 5-chloro-2,4-dihydroxypyridine (CDHP), enhanced the antiproliferative effect of 5-FU and IFN-alpha on KYN-3 approximately 4-fold. However, the synergistic effects of 5-FU and IFN-alpha on HAK-1A and KYN-2 were not affected by CDHP. The antiproliferative effect of 5-FU could thus be modulated by IFN-alpha, possibly through DPD expression, in HCC cells. Inhibition of DPD activity by CDHP may enhance the efficacy of IFN-alpha and 5-FU combination therapy in patients with HCC showing resistance to this therapy.
Oie
Shinji
S
Station-II for Collaborative Research, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan 812-8582. oh9906ie@qa2.so-net.ne.jp
Ono
Mayumi
M
Fukushima
Hiroto
H
Hosoi
Fumihito
F
Yano
Hirohisa
H
Maruyama
Yuichiro
Y
Kojiro
Masamichi
M
Terada
Tadafumi
T
Hirano
Kazuyuki
K
Kuwano
Michihiko
M
Yamada
Yuji
Y
D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil