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Additive effect of sirolimus and anti‐death receptor 5 agonistic antibody against hepatocellular carcinoma
Author(s) -
Kawahara Toshiyasu,
Toso Christian,
Yamaguchi Keisuke,
Cader Sonia,
Douglas Don.,
Nourbakhsh Mahra,
Lewis Jamie T.,
Churchill Thomas A.,
Yagita Hideo,
Kneteman Norman M.
Publication year - 2013
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12275
Subject(s) - sirolimus , medicine , in vivo , hepatocellular carcinoma , antibody , transplantation , pharmacology , cancer research , immunology , biology , microbiology and biotechnology
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 ( mA b) on HCC. Methods We first assessed the side effects of anti‐DR5 mA b administration in vivo by giving various doses of anti‐DR5 mA b. 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 mA b 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 mA b alone, (3) sirolimus alone and (4) anti‐DR5 mA b + sirolimus. Results Anti‐DR5 mA b (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 mA b lysed Hepa1‐6 and Huh7 cells in a dose‐dependent manner, and combinations of sirolimus and anti‐DR5 mA b 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 mA b has a significant effect against HCC. This strategy represents a potential novel approach for the management of HCC.