Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study
- ArchimMed (France)
- University of Paris 7-Denis Diderot, Department of Pathology, Faculty of Medicine, AP-HP Hopital Lariboisiere (France)
- Universite Paris Sud, Faculte de Pharmacie, UMR CNRS 8612, IFR 141-ITFM (France)
- AP-HP/INRA, Centre de Recherche En Imagerie Interventionnelle (France)
- AP-HP Hopital Ambroise Pare, Department of Interventional Radiology (France)
The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.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. 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. 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.
- OSTI ID:
- 22156518
- Journal Information:
- Cardiovascular and Interventional Radiology, Vol. 36, Issue 1; Other Information: Copyright (c) 2013 Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE); Article Copyright (c) 2012 Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE); Country of input: International Atomic Energy Agency (IAEA); ISSN 0174-1551
- Country of Publication:
- United States
- Language:
- English
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