title: Alteration of dihydropyrimidine dehydrogenase expression by IFN-alpha affects the antiproliferative effects of 5-fluorouracil in human hepatocellular carcinoma cells.
abstract: 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.
authors: Station-II for Collaborative Research, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan 812-8582. oh9906ie@qa2.so-net.ne.jp
authors: Shinji
authors: S
authors: Oie
authors: Mayumi
authors: M
authors: Ono
authors: Hiroto
authors: H
authors: Fukushima
authors: Fumihito
authors: F
authors: Hosoi
authors: Hirohisa
authors: H
authors: Yano
authors: Yuichiro
authors: Y
authors: Maruyama
authors: Masamichi
authors: M
authors: Kojiro
authors: Tadafumi
authors: T
authors: Terada
authors: Kazuyuki
authors: K
authors: Hirano
authors: Michihiko
authors: M
authors: Kuwano
authors: Yuji
authors: Y
authors: Yamada
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil