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Research Articles

Alteration of dihydropyrimidine dehydrogenase expression by IFN- affects the antiproliferative effects of 5-fluorouracil in human hepatocellular carcinoma cells

¹ Station-II for Collaborative Research and ² Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; ³ Personalized Medicine Research Laboratory and ⁴ Drug Discovery Laboratory, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan; ⁵ Research Center for Innovative Cancer Therapy and ⁶ Department of Pathology, Kurume University School of Medicine, Kurume, Japan; and ⁷ Laboratory of Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan

Requests for reprints: Shinji Oie, Station-II for Collaborative Research, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan 812-8582. Phone: 81-92-642-6295; Fax: 81-92-642-6295. E-mail: oh9906ie{at}qa2.so-net.ne.jp

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- on hepatocellular carcinoma (HCC) cells in culture and asks whether IFN- could affect DPD expression. The combined action of IFN- and 5-FU on three HCC lines was quantified by a combination index method. Coadministration of IFN- 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- but were down-regulated in HAK-1A and KYN-2. The expression of thymidylate synthase mRNA and protein was down-regulated by IFN- 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- on KYN-3 4-fold. However, the synergistic effects of 5-FU and IFN- on HAK-1A and KYN-2 were not affected by CDHP. The antiproliferative effect of 5-FU could thus be modulated by IFN-, possibly through DPD expression, in HCC cells. Inhibition of DPD activity by CDHP may enhance the efficacy of IFN- and 5-FU combination therapy in patients with HCC showing resistance to this therapy. [Mol Cancer Ther 2007;6(8):2310–8]

Grant support: Health and Labour Sciences Research grants of Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare, Japan and the 21st Century COE Program for Medical Sciences, Kurume University, supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/15/06; revised 4/22/07; accepted 6/12/07.