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Clinical Cancer Research Vol. 6, 2881-2890, July 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Augmentation of Antitumor Activity of 5-Fluorouracil by Interferon {alpha} Is Associated with Up-Regulation of p27Kip1 in Human Hepatocellular Carcinoma Cells1

Hidetoshi Eguchi, Hiroaki Nagano, Hirofumi Yamamoto, Atsushi Miyamoto, Motoi Kondo, Keizo Dono, Shoji Nakamori, Koji Umeshita, Masato Sakon2 and Morito Monden

Department of Surgery II, Osaka University Medical School, Osaka 565-0871, Japan

Several clinical trials have demonstrated the effectiveness of combination therapy with 5-fluorouracil (5-FU) and IFN-{alpha} in colon cancer, hepatocellular carcinoma (HCC), and other malignancies. In our preliminary clinical studies, we have observed outstanding effects with this combination therapy in patients with advanced HCC. However, the underlying mechanism by which IFN-{alpha} modulates the effects of 5-FU is unknown. We, therefore, conducted a mechanistic study using two HCC cell lines, PLC/PRF/5 and HuH7. IFN-{alpha} significantly enhanced the growth inhibitory effect of 5-FU in PLC/PRF/5 cells but not in HuH7 cells, and the isobolographic analysis indicated that this effect was synergistic. Flow cytometric analysis showed a delay in the progression of G0-G1 to S phase in PLC/PRF/5, and a sustained induction of the cyclin-dependent kinase inhibitor p27Kip1 and down-regulation of cyclin D1 was observed. Moreover, increased expression of p27Kip1 was associated with reduced CDK-2-associated kinase activity. Another difference in the two cell types was that PLC/PRF/5 expressed abundant IFN receptors, but HuH7 did not. Apoptosis assays were not helpful in explaining the mechanism. Our results suggest that the synergistic effects of 5-FU and IFN-{alpha} may in part be attributable to alterations in cell cycle progression via up-regulation of p27Kip1.




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Molecular Cancer Research Cancer Prevention Research
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