title: Hepatic arterial infusion but not systemic application of cetuximab in combination with oxaliplatin significantly reduces growth of CC531 colorectal rat liver metastases.
abstract: OBJECTIVE
  Systemic chemotherapy still represents the gold standard in the treatment of irresectable colorectal liver metastases. Modern anticancer agents like the monoclonal antibody cetuximab have improved the outcome of patients in clinical studies. As hepatic arterial infusion (HAI) is capable to potentially increase the anticancer effect of cytostatics, we herein studied whether HAI of cetuximab (CE) as a single agent or in combination with oxaliplatin (OX) exerts increased anticancer effects compared to the systemic application (SYS) of the drugs.
  
  
  METHODS
  WAG/Rij rats were randomized to eight groups and underwent 10 days after subcapsular hepatic tumor implantation either HAI or SYS of CE, OX, or the combination of both agents (CE + OX). Saline-treated animals served as controls. Tumor volume was measured at days 10 and 13 using three-dimensional ultrasound. On day 13, liver and tumor tissue was sampled for histological and immunohistochemical analysis.
  
  
  RESULTS
  In controls, the tumor volume significantly increased from day 10 to 13. Application of OX alone via HAI or SYS did not inhibit tumor growth compared to controls. SYS of CE or CE + OX did also not reduce tumor growth. In contrast, HAI of CE and CE + OX significantly inhibited tumor growth. HAI of CE significantly reduced tumor vascularization as measured by the number of platelet endothelial cell adhesion molecule-1-positive cells and significantly increased the number of apoptotic tumor cells as measured by the cellular caspase-3 expression.
  
  
  CONCLUSIONS
  HAI of CE and CE + OX reduces tumor growth of colorectal rat liver metastases involving the inhibition of angiogenesis and induction of tumor cell apoptosis.
authors.affiliation: Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, 66421 Homburg/Saar, Germany. jens.sperling@med.uni-goettingen.de
authors.forename: Jens
authors.initials: J
authors.lastname: Sperling
authors.forename: Thilo
authors.initials: T
authors.lastname: Schäfer
authors.forename: Anna
authors.initials: A
authors.lastname: Benz-Weißer
authors.forename: Christian
authors.initials: C
authors.lastname: Ziemann
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schilling
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006499:Hepatic Artery / Q000187:drug effects / Q000473:pathology*; D007261:Infusions, Intra-Arterial; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077150:Oxaliplatin; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D000077150:Oxaliplatin; D000068818:Cetuximab