title: Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.
abstract: OBJECTIVE
  Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies.
  
  
  METHODS
  C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine.
  
  
  RESULTS
  FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS.
  
  
  CONCLUSIONS
  We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. s.m.robinson@ncl.ac.uk
authors.forename: S M
authors.initials: SM
authors.lastname: Robinson
authors.forename: J
authors.initials: J
authors.lastname: Mann
authors.forename: A
authors.initials: A
authors.lastname: Vasilaki
authors.forename: J
authors.initials: J
authors.lastname: Mathers
authors.forename: A D
authors.initials: AD
authors.lastname: Burt
authors.forename: F
authors.initials: F
authors.lastname: Oakley
authors.forename: S A
authors.initials: SA
authors.lastname: White
authors.forename: D A
authors.initials: DA
authors.lastname: Mann
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D000975:Antioxidants / Q000008:administration & dosage; D002453:Cell Cycle; D015179:Colorectal Neoplasms / Q000188:drug therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000633:toxicity; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D002955:Leucovorin / Q000633:toxicity; D008103:Liver Cirrhosis / Q000139:chemically induced; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D018384:Oxidative Stress; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced
chemical_list: D000975:Antioxidants; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D018836:Inflammation Mediators; D009944:Organoplatinum Compounds; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil
keywords: ALP; ALT; AST; BHA; CRLM; CXCL1/2; Chemotherapy induced liver injury; Colorectal liver metastases; GAPDH; H&E; HPF; IL-6; MCP1; N-acetylcysteine; NAC; NAD(P)H dehydrogenase 1; NQO1; NRF2; Oxaliplatin; PAI-1; PAR 1/2; PCNA; SOS; STAT3; Sinusoidal obstruction syndrome; TXN1; VEGF-A/B/C; VEGFR-1/2; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; butylated hydroxyanisole; chemokine (C-X-C motif) ligand 1/2; colorectal liver metastases; gyceraldehyde 3-phosphate dehydrogenase; haematoxylin and eosin; high powered field; i.p.; interleukin 6; intraperitoneal; monocyte chemotactic protein-1; nuclear factor (erythroid-derived 2)-like 2; phosphorylated form of the H2A histone family, member X; plasminogen activatior inhibitor 1; proliferating cell nuclear antigen; protease activated receptor 1/2; signal transducer and activator of transcription 3; sinusoidal obstruction syndrome; thioredoxin 1; vWF; vascular endothelial growth factor A/B/C; vascular endothelial growth factor receptor ½; von Willebrand factor; γH2AX