Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy

• Published in: Liver international 2011-03, Vol.31 (3), p.313-321
• Main Authors: Rickenbacher, Andreas, DeOliveira, Michelle L., Tian, Yinghua, Jang, Jae Hwi, Riener, Marc-Oliver, Graf, Rolf, Moritz, Wolfgang, Clavien, Pierre-Alain
• Format: Article
• Language: English
• Subjects: 5-fluorouracyl; Alanine Transaminase - blood; Animal models; Animals; Antineoplastic Combined Chemotherapy Protocols - toxicity; Aspartate Aminotransferases - blood; Blood cells; Cell survival; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Chemotherapy; Colorectal cancer; Disease Models, Animal; Drugs; Enzymes; Fatty Liver - complications; Fatty Liver - pathology; gemcitabine; Hepatectomy; Inflammation; Injuries; Irinotecan; Ki-67 Antigen - metabolism; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver cancer; liver regeneration; Liver Regeneration - drug effects; Liver Regeneration - physiology; Mice; Mice, Inbred C57BL; oxaliplatin; Parenchyma; Proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - metabolism; Side effects; steatosis; Surgery
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/j.1478-3231.2010.02446.x

Background: New chemotherapy regimens are increasingly used in metastatic colorectal cancer to the liver before surgery. Some clinical observations have suggested that chemotherapy may affect liver regeneration. Aims: The aim of this study was to evaluate liver damage and liver regeneration after chemotherapy treatment in a model of partial hepatectomy. Methods: C57BL/6 mice were repeatedly treated with intraperitoneal injections of either saline or different chemotherapy regimens including the drugs 5‐fluorouracyl (5‐FU), irinotecan, oxaliplatin, gemcitabine and combined treatments with 5‐FU/irinotecan, 5‐FU/oxaliplatin. A 70% partial hepatectomy was performed 1 week after the last injection. Ki‐67 and PCNA immunohistochemistry were performed to assess liver regeneration, serum liver enzymes and histology analysis to evaluate injury. Results: A variety of chemotherapeutic agents used at maximum tolerated doses compatible with survival affected body weight and blood cell levels. However, these regimens did not affect liver injury before and after hepatectomy nor did they impair liver regeneration. Liver histology showed no steatosis, fibrosis or inflammation before hepatectomy. We therefore tested whether chemotherapy in presence of diet‐induced steatosis may trigger injury. Even under these conditions, we did not observe histological signs of inflammation or sinusoidal injury. Conclusions: Liver injury and liver regeneration are not impaired after neoadjuvant chemotherapy with 5‐FU, irinotecan, oxaliplatin and gemcitabine in non‐tumoural liver parenchyma. In addition, combined treatments disclose no adverse effects on liver regeneration. Chemotherapy alone induces no histological alterations even in the presence of steatosis.