title: An experimental study to identify the potential role of pharmacogenomics in determining the occurrence of oxaliplatin-induced liver injury.
abstract: BACKGROUND
  Oxaliplatin-based chemotherapy has been linked to the development of sinusoidal obstruction syndrome (SOS), which is detrimental to outcome after liver resection for colorectal liver metastases (CLM). The aim of this study was to determine how the expression of genes involved in the transport and metabolism of FOLFOX chemotherapy impacts on tissue injury in a murine model of CLM.
  
  
  METHODS
  Experimental CLM was established in C57/B16 mice and treated with FOLFOX chemotherapy. After 3 weeks, the animals were killed and RNA extracted from liver, spleen and tumour tissue. DNA damage was assessed by immunohistochemistry for γH2AX. Gene expression was determined by reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  FOLFOX treatment was associated with an increase in the number of γH2AX-positive cells in both the spleen (P < 0.01) and tumour tissue (P < 0.01), but not the liver. Tissue resistance to injury following FOLFOX was associated with high expression of the copper transporter ATP7B. Differences in the expression of genes related to 5-fluorouracil metabolism or DNA repair did not correlate with the severity of tissue injury.
  
  
  CONCLUSIONS
  High levels of expression of ATP7B are associated with resistance to tissue injury following FOLFOX chemotherapy. Polymorphisms in the ATP7B gene may explain varying susceptibility to SOS among patients following oxaliplatin-based chemotherapy.
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. s.m.robinson@ncl.ac.uk
authors: Stuart M
authors: SM
authors: Robinson
authors: Jelena
authors: J
authors: Mann
authors: Derek M
authors: DM
authors: Manas
authors: Derek A
authors: DA
authors: Mann
authors: Steven A
authors: SA
authors: White
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000073840:Copper-Transporting ATPases; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000235:genetics / Q000378:metabolism; D002955:Leucovorin / Q000378:metabolism / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000633:toxicity*; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D010641:Phenotype
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D006657:Histones; D009944:Organoplatinum Compounds; C475961:gamma-H2AX protein, mouse; D000077150:Oxaliplatin; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D002955:Leucovorin; D005472:Fluorouracil