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

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.

• Authors: Toshiyasu Kawahara, Christian Toso, Keisuke Yamaguchi, Sonia Cader, Donna N Douglas, Mahra Nourbakhsh, Jamie T Lewis, Thomas A Churchill, Hideo Yagita, Norman M Kneteman
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 33 Issue 9 Pg. 1441-8 (Oct 2013) ISSN: 1478-3231 [Electronic] United States
• PMID: 23895107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Tetrazolium Salts
• Thiazoles
• thiazolyl blue
• Sirolimus

Topics

• Analysis of Variance
• Animals
• Antibodies, Monoclonal (adverse effects, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Humans
• Liver Neoplasms (drug therapy)
• Mice
• Mice, Inbred C57BL
• Receptors, TNF-Related Apoptosis-Inducing Ligand (immunology)
• Sirolimus (pharmacology)
• Tetrazolium Salts
• Thiazoles