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Liver Int. 2013 Oct;33(9):1441-8. doi: 10.1111/liv.12275. Epub 2013 Jul 29.

Additive effect of sirolimus and anti-death receptor 5 agonistic antibody against hepatocellular carcinoma.

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  • 1Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Abstract

BACKGROUND & AIMS:

Despite careful patient selection, hepatocellular carcinoma (HCC) recurs in 10-20% of cases after liver transplantation, and the use of potent adjuvant anticancer drugs would be welcome. The aim of this study was to evaluate the efficiency of a combined therapy of rapamycin (sirolimus) and anti-death receptor (DR)5 monoclonal antibody (mAb) on HCC.

METHODS:

We first assessed the side effects of anti-DR5 mAb administration in vivo by giving various doses of anti-DR5 mAb. Cell proliferation assays were then performed using mouse Hepa1-6 cells or human Huh7 cells to quantify the relative cell viability under various concentrations of sirolimus, anti-DR5 mAb or a combination. Next, one million Hepa1-6 cells were transplanted into C.B17-SCID-beige mice subcutaneously, and four groups were created: (1) untreated, (2) anti-DR5 mAb alone, (3) sirolimus alone and (4) anti-DR5 mAb + sirolimus.

RESULTS:

Anti-DR5 mAb (200 and 300 μg/day) induced liver dysfunction with partial necrosis of the liver, but 100 μg/day was well tolerated with transaminitis, but normal bilirubin and only minor histological liver damage. In vitro, anti-DR5 mAb lysed Hepa1-6 and Huh7 cells in a dose-dependent manner, and combinations of sirolimus and anti-DR5 mAb demonstrated an additive effect. In vivo studies demonstrated that tumour sizes were significantly smaller in the combined therapy group than in the monotherapy groups.

CONCLUSIONS:

Combining sirolimus and low-dose anti-DR5 mAb has a significant effect against HCC. This strategy represents a potential novel approach for the management of HCC.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

KEYWORDS:

Death receptor 5; hepatocellular carcinoma; liver transplantation; rapamycin

PMID:
23895107
[PubMed - indexed for MEDLINE]
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