Hepatic regeneration in a rat model is impaired by chemotherapy agents used in metastatic colorectal cancer.
OBJECTIVE
Administering Oxaliplatin prior to resection of colorectal liver metastases often induces a Sinusoidal Obstruction Syndrome (SOS), which can affect postoperative patient outcome. Bevacizumab (Anti-VEGF-A) can decrease the severity of SOS and the associated risk of postoperative liver failure. We investigated the impact of both Oxaliplatin (Oxali) and Bevacizumab on liver regeneration in a rat model.


METHODS
Male Wistar rats underwent a 70% partial hepatectomy (PH) 3 days after a 2 ml intraperitoneal injection of either saline (controls, n = 17), or Oxaliplatin 10, 20 or 50 mg/kg, 5-Fluorouracil 100 mg/kg (5-FU) and Bevacizumab 5 or 10 mg/kg in various combinations (total 98 rats, 11 groups, n = 5-18/group). Liver regeneration was assessed by remnant liver weight recovery and cell proliferation by immunodetection of BrDU incorporation (days 1, 2, 3, 7). Hepatic mRNA expression levels of VEGF-A and of its 2 receptors (Flt-1 and KDR) were quantified by PCR technique.


RESULTS
Liver regeneration was impaired for 3 days post PH by Oxali 20 alone and Oxali 10 + 5-FU, without any rescue effect by neither Bevacizumab 5 nor 10 mg/kg. Unlike in humans, there were no sinusoidal changes. VEGF-A mRNA expression and receptor 2 (KDR) expressions decreased 24 h post PH in a similar fashion in controls, Oxali 20 and Oxali 10 + 5-FU groups. All groups had recovered over 60% of their liver weight by day 7.


CONCLUSIONS
Oxaliplatin causes early hepatocyte proliferation impairment post PH, unaffected by Bevacizumab and unexplained by changes in VEGF-A signalling in a Wistar rat model.
Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Cliniques universitaires Saint-Luc, Hippocrate Avenue, 10, 1200 Brussels, Belgium. Electronic address: hubertcatherine2000@yahoo.fr.
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Hubert
Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Cliniques universitaires Saint-Luc, Hippocrate Avenue, 10, 1200 Brussels, Belgium.
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Dahrenmoller
Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Cliniques universitaires Saint-Luc, Hippocrate Avenue, 10, 1200 Brussels, Belgium.
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Marique
Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Cliniques universitaires Saint-Luc, Hippocrate Avenue, 10, 1200 Brussels, Belgium.
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Jabbour
Laboratory of Experimental Surgery, Institut de Recherche Expérimentale et Clinique Université catholique de Louvain (UCL), Hippocrate Avenue, 10, 1200 Brussels, Belgium.
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Gianello
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCL), Avenue E Mounier 53, 1200 Brussels, Belgium.
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Leclercq
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000556:secondary; D004359:Drug Therapy, Combination; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009374:Neoplasms, Experimental; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D051381:Rats; D017208:Rats, Wistar
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab
Bevacizumab; Chemotherapy; Liver regeneration