title: Toxicity of doxorubicin on pig liver after chemoembolization with doxorubicin-loaded microspheres: a pilot DNA-microarrays and histology study.
abstract: OBJECTIVE
  The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.
  
  
  METHODS
  The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process.
  
  
  RESULTS
  At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration.
  
  
  CONCLUSIONS
  DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.
authors.affiliation: ArchimMed, 12 Rue Charles de Gaulle, 78350, Jouy-en-Josas, France. valentin.verret@archimmed.com
authors.forename: Valentin
authors.initials: V
authors.lastname: Verret
authors.forename: Julien
authors.initials: J
authors.lastname: Namur
authors.forename: Saïda Homayra
authors.initials: SH
authors.lastname: Ghegediban
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.forename: Laurence
authors.initials: L
authors.lastname: Moine
authors.forename: Michel
authors.initials: M
authors.lastname: Bonneau
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelage
authors.forename: Alexandre
authors.initials: A
authors.lastname: Laurent
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D004337:Drug Carriers / Q000494:pharmacology; D006499:Hepatic Artery / Q000187:drug effects / Q000473:pathology*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D008863:Microspheres; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010865:Pilot Projects; D011897:Random Allocation; D012680:Sensitivity and Specificity; D034421:Sus scrofa; D013552:Swine
chemical_list: D004337:Drug Carriers; D004317:Doxorubicin