Bevacizumab impairs hepatocyte proliferation after partial hepatectomy in a rabbit model.

2012 
Background: Bevacizumab is used to treat patients with metastatic colorectal cancer, including those who will undergo liver surgery. The effects of this agent on the regenerative capacity of the liver are unclear. We used a rabbit model of partial hepatectomy to assess the effects of bevacizumab on hepatocyte replication and the expression of genes relevant to angiogenesis and proliferation. Materials and Methods: Thirty rabbits underwent 28% hepatectomy. At the end of the procedure, animals were blindly randomized into two groups. A control group was injected i.v. with saline and the other group with bevacizumab at 50 mg/kg. Three rabbits from each group were sacrificed at days 2, 3, 5, 7 and 14 after hepatectomy. Livers were collected and processed. Hepatocyte proliferation was evaluated by Ki-67 immunostaining and apoptosis by caspase-3 activity. Gene expression of Vascular endothelial growth factor (VEGF), Hepatocyte growth factor (HGF) and Inhibitor α of nuclear factor-κB (IκBα) was determined by quantitative Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Results: Compared with controls, hepatocyte proliferation in bevacizumab-treated animals was decreased 1.8-fold at day 3, 1.6-fold at day 5 and 2.1-fold at day 14. Neoangiogenesis began after day 5, with a peak of VEGF mRNA evident at day 7 in both groups. Expression of IκBα, a transcriptional target of Nuclear Factor-κB, increased significantly from baseline only in the control group: at day 2, expression was 179% of the day 0 value in controls versus 112% in the bevacizumab group. Expression of HGF and caspase-3 was similar in the two groups and remained stable over time. Conclusion: A single i.v. injection of bevacizumab impaired hepatocyte proliferation in a rabbit model of partial hepatectomy. The treatment of colorectal liver metastases (CLM) represents a challenge. Surgical resection is potentially curative, with a reported 5-year survival of 25% to 50% (1), but only 10-20% of patients with CLM are candidates for hepatic surgery (2). There is evidence that neoadjuvant chemotherapy (frequently given in combination with agents targeted at growth factors or their receptors) can render initially unresectable disease amenable to potentially curative surgery. However, it has been suggested that major hepatic resection after such therapy might be associated with increased postoperative morbidity due to a delay in the recovery of hepatic function (3, 4). This could result either from the direct hepatotoxicity of the used agents or, indirectly, from impaired liver regeneration (LR).
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