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Sorafenib inhibits liver regeneration in rats
Kasper Jarlhelt Andersen1, Anders Riegels Knudsen, Anne-Sofie Kannerup
1Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Background:
Sorafenib is a multikinase inhibitor with antiangiogenic and antiproliferative properties, approved for the treatment of hepatocellular carcinoma. The effect of Sorafenib on liver regeneration in healthy rats was investigated.
Methods:
Sixty Wistar rats received either Sorafenib (group S; 15 mg/kg) or placebo for 14 days prior to resection and until sacrifice. After a 70% partial hepatectomy, the rats were euthanized on post-operative days (POD) 2, 4 or 8. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using stereological methods on sections prepared by systematic uniform random sampling.
Results:
Seven animals (12%) died after surgery. Death rates were similar in treated rats and controls. At hepatectomy, the body weight was significantly lower in group S rats. The liver weight and regeneration rates were lower in group S rats on PODs 2, 4 and 8. Hepatocyte proliferation was significantly lower in group S animals on PODs 2 and 4. Alanine aminotransferase ALAT was significantly higher in the Sorafenib-treated group on PODs 2, 4 and 8. Alkaline phosphatase ALP and bilirubin levels were similar in the two groups, although bilirubin was elevated in group S rats on POD 8.
Conclusion:
In this rat model, Sorafenib did not increase post-hepatectomy mortality, but was associated with a significant impaired liver weight gain, regeneration rates and hepatocyte proliferation.
Insights
Sorafenib, used for liver cancer, did not increase deaths after liver surgery in rats. However, it did impair liver regeneration and growth in this animal model.
Area of Science:
- Hepatology
- Pharmacology
- Surgical Research
Background:
- Sorafenib is a multikinase inhibitor approved for hepatocellular carcinoma treatment.
- It possesses antiangiogenic and antiproliferative properties.
- Its impact on liver regeneration following hepatectomy was unexplored.
Purpose of the Study:
- To investigate the effects of Sorafenib on liver regeneration in healthy rats post-partial hepatectomy.
- To assess Sorafenib's influence on hepatocyte proliferation and liver recovery markers.
Main Methods:
- Sixty Wistar rats were divided into Sorafenib (15 mg/kg) and placebo groups.
- A 70% partial hepatectomy was performed, followed by drug administration for 14 days.
- Hepatocyte proliferation was quantified using Ki-67 immunohistochemistry and stereology.
Main Results:
- Mortality rates were comparable between Sorafenib and placebo groups.
- Sorafenib-treated rats exhibited reduced liver weight, regeneration rates, and hepatocyte proliferation on PODs 2, 4, and 8.
- Elevated alanine aminotransferase (ALAT) levels were observed in the Sorafenib group.
Conclusions:
- Sorafenib did not elevate post-hepatectomy mortality in this rat model.
- Sorafenib significantly impaired liver regeneration, liver weight gain, and hepatocyte proliferation.
- These findings suggest potential risks of Sorafenib use in patients undergoing liver resection.
