Oncotarget

Research Papers:

Bevacizumab exacerbates sinusoidal obstruction syndrome (SOS) in the animal model and increases MMP 9 production

Azin Jafari, Hanno Matthaei, Sven Wehner, Tolga Tonguc, Jörg C. Kalff and Steffen Manekeller _

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Oncotarget. 2018; 9:21797-21810. https://doi.org/10.18632/oncotarget.25021

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Abstract

Azin Jafari1, Hanno Matthaei1, Sven Wehner1, Tolga Tonguc1, Jörg C. Kalff1 and Steffen Manekeller1

1Department of Surgery, University Hospital Bonn, Germany

Correspondence to:

Steffen Manekeller, email: [email protected]

Keywords: SOS; sinusoidal obstruction syndrome; bevacizumab; colorectal cancer; CRC

Received: December 21, 2017     Accepted: March 17, 2018     Published: April 24, 2018

ABSTRACT

Background: Thanks to modern multimodal treatment the ouctome of patients with colorectal cancer has experienced significant improvements. As a downside, agent specific side effects have been observed such as sinusoidal obstruction syndrome (SOS) after oxaliplatin chemotherapy (OX). Bevazicumab targeting VEGF is nowadays comprehensively used in combination protocols with OX but its impact on hepatotoxicity is thus far elusive and focus of the present study.

Results: After MCT administration 67% of animals developed SOS. GOT serum concentration significantly increased in animals developing SOS (p < 0.001). Subsequent to MCT administration 100% of animals treated with Anti-VEGF developed SOS. In contrast, animals receiving VEGF developed SOS merely in 40% while increasing the VEGF dose led to a further decrease in SOS development to 25%. MMP 9 concentration in animals developing SOS was significantly higher compared to controls (p < 0,001). Additional treatment with Anti-VEGF increased the MMP 9 concentration significantly (p < 0,05).

Conclusions: Preservation of liver function is a central goal in both curative and palliative treatment phases of patients with CRC. Thus, knowledge about hepatotoxic side effects of chemotherapeutic and biological agents is crucial. From the results it can be concluded that Anti-VEGF exacerbates SOS paralleled by MMP 9 production. Therefore, OX-Bevacizumab combination therapies should be administered with caution, especially if liver parenchyma damage is apparent.

Methods: Male Sprague-Dawley rats were gavaged Monocrotaline (MCT) to induce SOS. Recombinant VEGF or an Anti-VEGF antibody was administered to MCT-treated rats and the hepatotoxic effect monitored in defined time intervals. MMP 9 expression in the liver was measured by ELISA.


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