Postoperative but not preoperative treatment with sorafenib inhibits liver regeneration in rats.
BACKGROUND
Sorafenib, a multikinase inhibitor, has been shown to halt the growth of hepatocellular carcinoma. The aim of the present study was to investigate the effect of Sorafenib on liver regeneration in healthy rats.


METHODS
In two substudies we examined the effect of pre- or post-operative treatment with Sorafenib (15 mg/kg/d). Wistar rats (n = 120) received either Sorafenib (S) or placebo (P). After 70% partial hepatectomy, the rats were euthanized on postoperative days 2, 4, or 8. Body weight and liver weight were recorded and regeneration rate (RR) calculated. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using unbiased stereological methods.


RESULTS
Eleven animals (9%) died after surgery. In the preoperative substudy, lower body weight gains during the gavage period in the S group were found. No difference between groups S and P regarding liver weight gain, liver RRs, and hepatocyte proliferation on postoperative days 2 and 4 were found. In the postoperative substudy, significantly lower values of liver weight gain, liver RRs, and hepatocyte proliferation were found in the S group.


CONCLUSIONS
In our rat model, Sorafenib did not increase posthepatectomy mortality. Postoperative treatment significantly impaired liver regeneration. Preoperative treatment impaired body weight during the gavage period, but was without effect on liver regeneration.
Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: kasperjarlheltandersen@gmail.com.
Kasper Jarlhelt
KJ
Andersen
Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Anders Riegels
AR
Knudsen
Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Anne-Sofie
AS
Kannerup
Stereology & Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark.
Jens Randel
JR
Nyengaard
Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
Stephen
S
Hamilton-Dutoit
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
Morten
M
Ladekarl
Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Frank Viborg
FV
Mortensen
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006498:Hepatectomy / Q000401:mortality; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008115:Liver Regeneration / Q000187:drug effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011184:Postoperative Period; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077157:Sorafenib
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
Hepatocyte proliferation; Immunohistochemistry; Liver regeneration; Liver resection; Rat; Stereology