CardioVascular and Interventional Radiology

, Volume 36, Issue 1, pp 204–212

Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study

  • Valentin Verret
  • Julien Namur
  • Saïda Homayra Ghegediban
  • Michel Wassef
  • Laurence Moine
  • Michel Bonneau
  • Jean-Pierre Pelage
  • Alexandre Laurent
Laboratory Investigation

DOI: 10.1007/s00270-012-0369-1

Cite this article as:
Verret, V., Namur, J., Ghegediban, S.H. et al. Cardiovasc Intervent Radiol (2013) 36: 204. doi:10.1007/s00270-012-0369-1

Abstract

Purpose

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.

Keywords

Drug-loaded microspheres Doxorubicin Liver chemoembolization DNA-microarrays 

Supplementary material

270_2012_369_MOESM1_ESM.xls (82 kb)
Supplementary material 1 (XLS 82 kb)

Copyright information

© Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2012

Authors and Affiliations

  • Valentin Verret
    • 6
  • Julien Namur
    • 6
  • Saïda Homayra Ghegediban
    • 6
  • Michel Wassef
    • 1
  • Laurence Moine
    • 2
  • Michel Bonneau
    • 3
  • Jean-Pierre Pelage
    • 4
  • Alexandre Laurent
    • 3
    • 5
  1. 1.Department of Pathology, Faculty of Medicine, AP-HP Hôpital LariboisièreUniversity of Paris 7—Denis DiderotParisFrance
  2. 2.Faculté de Pharmacie, UMR CNRS 8612, IFR 141-ITFMUniversité Paris SudChâtenay-MalabryFrance
  3. 3.Centre de Recherche En Imagerie InterventionnelleAP-HP/INRAJouy-en-JosasFrance
  4. 4.Department of Interventional RadiologyAP-HP Hôpital Ambroise ParéBoulogne-BillancourtFrance
  5. 5.Department of Neuroradiology, Faculty of Medicine, AP-HP Hôpital LariboisèreUniversity of Paris 7—Denis DiderotParisFrance
  6. 6.ArchimMedJouy-en-JosasFrance