The effects of sorafenib on liver regeneration in a model of partial hepatectomy

• Published in: The Journal of surgical research Vol. 178; no. 1; pp. 242 - 247
• Main Authors: Kurniali, Peter C., MD, O'Gara, Katie, Wang, Xiaofei, MD, Wang, Li Juan, MD, Somasundar, Ponnandai, MD, Falanga, Vincent, MD, Espat, N. Joseph, MD, Katz, Steven C., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2012
• Subjects: Animals; Benzenesulfonates - pharmacology; BrdU; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - surgery; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Hepatectomy - methods; Hepatocytes - drug effects; Hepatocytes - physiology; Ki67; Liver Cirrhosis - drug therapy; Liver Cirrhosis - surgery; Liver Neoplasms - drug therapy; Liver Neoplasms - surgery; Liver regeneration; Liver Regeneration - drug effects; Liver Regeneration - physiology; Male; Mice; Mice, Inbred C57BL; Models, Animal; Niacinamide - analogs & derivatives; Partial hepatectomy; Phenylurea Compounds; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Sorafenib; Surgery; Partial hepatectomy; Ki67; Sorafenib; Liver regeneration; BrdU
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2012.01.033

Abstract Background Sorafenib is currently approved for advanced hepatocellular carcinoma (HCC) and is presently being studied as an adjuvant treatment for HCC following resection. The effects of sorafenib on liver regeneration have not been clearly defined. Our objective was to identify the effects of sorafenib on liver regeneration in a murine partial hepatectomy (PH) model. Materials and methods We performed PH in C57Bl/6 mice treated with a range of sorafenib doses with assessments at several time points. Liver sinusoidal endothelial cells (LSEC) and hepatocyte DNA synthesis and proliferation were assessed with 5-bromo-2′-deoxyuridine (BrdU) and Ki67 by flow cytometry and immunohistochemistry. Results Treatment with sorafenib did not result in any deaths following PH. When we measured BrdU uptake to assess DNA synthesis, there was a statistically significant increase at 48 h post-PH for nonfibrotic LSEC following treatment with 60 mg/kg of sorafenib. However, BrdU and Ki67 staining among LSEC and hepatocytes was not significantly affected by sorafenib at any of the other doses or time points. BrdU and Ki67 flow cytometry data correlated with immunohistochemistry findings and postoperative liver weights. Conclusion In a murine PH model, sorafenib did not alter the repair response of normal or fibrotic livers following PH as measured by changes in liver weight, DNA synthesis, and cellular proliferation. These findings suggest sorafenib administered following hepatic resection does not impair liver regeneration.