caa a22 4500 445338318 CHVBK 20180317142803.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1245/s10434-010-1310-y doi (NATIONALLICENCE)springer-10.1245/s10434-010-1310-y Tyrosine Kinase Inhibitor PTK/ZK Enhances the Antitumor Effects of Interferon-α/5-Fluorouracil Therapy for Hepatocellular Carcinoma Cells [Elektronische Daten] [Masahiro Murakami, Shogo Kobayashi, Shigeru Marubashi, Yoshito Tomimaru, Takehiro Noda, Hiroshi Wada, Hidetoshi Eguchi, Yutaka Takeda, Masahiro Tanemura, Koji Umeshita, Yuichiro Doki, Masaki Mori, Hiroaki Nagano] Purpose: There is no standardized treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus. We previously reported the efficacy of interferon-alpha and 5-fluorouracil combination (IFN/5-FU) therapy for these patients and the potential mechanism via the regulation of vascular endothelial growth factor (VEGF). In this study, we showed the VEGF-related effects of IFN/5-FU therapy using VEGF-receptor (VEGFR) selective inhibitor, PTK787/ZK222584 (PTK/ZK), in HCC cells. Methods: Using two VEGF secreting and VEGFR expressing human HCC cell lines, PLC/PRF/5 and HuH7, we performed growth inhibitory assays in vitro and in vivo, apoptosis assay, cell cycle analysis, and Western blot analysis for the mechanism, with or without PTK/ZK in IFN/5-FU therapy. Results: The combination of PTK/ZK and IFN/5-FU significantly inhibited cell growth in vitro and tended to reduce tumor growth in vivo in a HuH7 xenograft model in nude mice—in both cases without affecting VEGF secretion. PTK/ZK enhanced the IFN/5-FU induced apoptosis, based on increased proteins levels of Bax and reduced Bcl-xL and Bcl-2. Cell cycle analysis showed different results between the HCC cell lines following the combination therapy, possibly due to differences in p21 protein. Conclusions: VEGF signaling inhibition would support an antitumor effect of IFN/5-FU therapy against HCC cell lines via induction of apoptosis and cell cycle delay. Society of Surgical Oncology, 2010 Murakami Masahiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Kobayashi Shogo Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Marubashi Shigeru Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Tomimaru Yoshito Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Noda Takehiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Wada Hiroshi Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Eguchi Hidetoshi Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Takeda Yutaka Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Tanemura Masahiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Umeshita Koji Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Doki Yuichiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Mori Masaki Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Nagano Hiroaki Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut Annals of Surgical Oncology Springer-Verlag 18/2(2011-02-01), 589-596 1068-9265 18:2<589 2011 18 10434 https://doi.org/10.1245/s10434-010-1310-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1245/s10434-010-1310-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Murakami Masahiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Kobayashi Shogo Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Marubashi Shigeru Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Tomimaru Yoshito Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Noda Takehiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Wada Hiroshi Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Eguchi Hidetoshi Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Takeda Yutaka Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Tanemura Masahiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Umeshita Koji Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Doki Yuichiro Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Mori Masaki Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 700 1- Nagano Hiroaki Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan aut NATIONALLICENCE 773 0- Annals of Surgical Oncology Springer-Verlag 18/2(2011-02-01), 589-596 1068-9265 18:2<589 2011 18 10434 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer