Reference - Detail
|Author||Kawahara T, Toso C, Yamaguchi K, Cader S, Douglas DN, Nourbakhsh M, Lewis JT, Churchill TA, Yagita H, Kneteman NM.|
|Title||Additive effect of sirolimus and anti-death receptor 5 agonistic antibody against hepatocellular carcinoma.|
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.
|MeSH||Analysis of Variance Animals Antibodies, Monoclonal / adverse effects Antibodies, Monoclonal / 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|
|WOS Category||GASTROENTEROLOGY & HEPATOLOGY|
|Human and Animal Cells|