• Tameyoshi Yamamoto, Hiroaki Nagano, Masato Sakon, Hisashi Wada, Hidetoshi Eguchi, Motoi Kondo, Bazarragchaa Damdinsuren, Hideo Ota, Masato Nakamura, Hiroshi Wada, Shigeru Marubashi, Atsushi Miyamoto, Keizo Dono, Koji Umeshita, Shoji Nakamori, Hideo Yagita, and Morito Monden.
• Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka, University, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
• Clin Cancer Res. 2004 Dec 1; 10 (23): 7884-95.

PurposeOur purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFNalpha and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC).Experimental DesignSusceptibility of HCC cell lines to TRAIL and/or 5-FU was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of 5-FU, IFNalpha, or both on the expression of TRAIL receptors (R1, R2, R3, and R4) on HCC cells or TRAIL in peripheral blood mononuclear cells (PBMC) were examined by flow cytometry. IFNalpha-induced cytotoxic effects of PBMC on HCC cell lines were examined by (51)Cr release assay. TRAIL expression in peripheral blood mononuclear cells and liver tissue from patients was examined by real-time reverse transcription-PCR or immunohistochemistry.ResultsHLE and HepG2 were sensitive to TRAIL, but HuH7, PLC/PRF/5, and HLF were resistant. 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines. TRAIL receptors on HCC cells were up-regulated by 5-FU, and IFNalpha induced TRAIL on CD4(+) T cells, CD14(+) monocytes, and CD56(+) NK cells. Treatment of effector cells by IFNalpha and target HCC cells by 5-FU enhanced the cytotoxicity of CD14(+) monocytes and CD56(+) NK cells against HCC cells via a TRAIL-mediated pathway. TRAIL mRNA overexpression was noted in PBMC of HCC patients who clinically responded to IFNalpha/5-FU combination therapy, and TRAIL(+) mononuclear cells were found in cancer tissue of a responder.ConclusionOur results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFNalpha and 5-FU combination therapy.

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