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RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver

Authors

  • Ji-Hua Shi MD,

    1. Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    3. Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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  • Shu-Zheng Liu MD,

    1. Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Lene Wierød PhD,

    1. Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Hanne Scholz PhD,

    1. Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Jarl Andreas Anmarkrud PhD,

    1. Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Henrik S. Huitfeldt MD, PhD,

    1. Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Shui-Jun Zhang MD, PhD,

    1. Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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  • Pål-Dag Line MD, PhD

    Corresponding author
    1. Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    • Chairman, Department of Transplantation, Oslo University Hospital, Rikshospitalet, 4950 Nydalen, 0424 Oslo, Norway. Fax: +47-23070510.===

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  • Conflict of interests: none declared.

Abstract

Background

Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration.

Objective

To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model.

Methods

Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers.

Results

Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes.

Conclusions

The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment. J. Surg. Oncol. 2013;107:393–401. © 2012 Wiley Periodicals, Inc.

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