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CardioVascular and Interventional Radiology

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01.02.2013 | Laboratory Investigation

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

verfasst von: Valentin Verret, Julien Namur, Saïda Homayra Ghegediban, Michel Wassef, Laurence Moine, Michel Bonneau, Jean-Pierre Pelage, Alexandre Laurent

Erschienen in: CardioVascular and Interventional Radiology | Ausgabe 1/2013

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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.

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Titel: Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study
verfasst von: Valentin Verret
Julien Namur
Saïda Homayra Ghegediban
Michel Wassef
Laurence Moine
Michel Bonneau
Jean-Pierre Pelage
Alexandre Laurent
Publikationsdatum: 01.02.2013
Verlag: Springer-Verlag
Erschienen in: CardioVascular and Interventional Radiology / Ausgabe 1/2013
Print ISSN: 0174-1551
Elektronische ISSN: 1432-086X
DOI: https://doi.org/10.1007/s00270-012-0369-1

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