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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 2/2011

01-02-2011 | Translational Research and Biomarkers

Tyrosine Kinase Inhibitor PTK/ZK Enhances the Antitumor Effects of Interferon-α/5-Fluorouracil Therapy for Hepatocellular Carcinoma Cells

Authors: Masahiro Murakami, MD, Shogo Kobayashi, MD, PhD, Shigeru Marubashi, MD, PhD, Yoshito Tomimaru, MD, Takehiro Noda, MD, PhD, Hiroshi Wada, MD, PhD, Hidetoshi Eguchi, MD, PhD, Yutaka Takeda, MD, PhD, Masahiro Tanemura, MD, PhD, Koji Umeshita, MD, PhD, Yuichiro Doki, MD, PhD, Masaki Mori, MD, PhD, Hiroaki Nagano, MD, PhD

Published in: Annals of Surgical Oncology | Issue 2/2011

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Abstract

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.
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Metadata
Title
Tyrosine Kinase Inhibitor PTK/ZK Enhances the Antitumor Effects of Interferon-α/5-Fluorouracil Therapy for Hepatocellular Carcinoma Cells
Authors
Masahiro Murakami, MD
Shogo Kobayashi, MD, PhD
Shigeru Marubashi, MD, PhD
Yoshito Tomimaru, MD
Takehiro Noda, MD, PhD
Hiroshi Wada, MD, PhD
Hidetoshi Eguchi, MD, PhD
Yutaka Takeda, MD, PhD
Masahiro Tanemura, MD, PhD
Koji Umeshita, MD, PhD
Yuichiro Doki, MD, PhD
Masaki Mori, MD, PhD
Hiroaki Nagano, MD, PhD
Publication date
01-02-2011
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 2/2011
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-010-1310-y

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