title: Bevacizumab impairs hepatocyte proliferation after partial hepatectomy in a rabbit model.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  A single i.v. injection of bevacizumab impaired hepatocyte proliferation in a rabbit model of partial hepatectomy.
authors.affiliation: Department of Surgical Oncology, Léon Bérard Centre, 28 rue Laennec, 69008 Lyon, France. dupre.aurelien@hotmail.fr
authors.forename: Aurelien
authors.initials: A
authors.lastname: Dupre
authors.forename: Andrea
authors.initials: A
authors.lastname: Paradisi
authors.forename: Stephan
authors.initials: S
authors.lastname: Langonnet
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gandini
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D000068258:Bevacizumab; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D008115:Liver Regeneration / Q000187:drug effects*; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D020672:I-kappa B Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D000068258:Bevacizumab; D017228:Hepatocyte Growth Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase