title: Daunorubicin does not induce immunohistochemically detectable endothelial dysfunction in rabbit aorta and femoral artery.
abstract: Anthracyclines are one of the most effective anticancer drugs ever developed, but their clinical use has been hampered by the risk of severe cardiotoxicity. In this study, we investigated whether rabbits exposed to a different cumulative dose of anthracycline suffer from immunohistochemically detectable vascular toxicity and endothelial dysfunction. Daunorubicin (3 mg/kg, i.e. 50 mg/m²) was administered i.v. to rabbits once weekly for 1-10 weeks to reach different cumulative doses of the drug (50-500 mg/m²), while control rabbits received saline. The rabbits were sacrificed either 24 hours or 7 days after reaching each particular cumulative dose, and aortas and right femoral arteries were collected for immunohistochemical analysis. Immunohistochemical analysis showed ICAM-1 staining in many aortas from both saline and daunorubicin-treated rabbits without any relationship to the anthracycline treatment. On the contrary, unlike in the lipopolysaccharide-treated or hypercholesterolemic rabbits, no distinct immunoreactivity for other markers of inflammation, oxidative and nitrosative stress (VCAM-1, 4-HNE, iNOS and nitrotyrosine) were detected in aortas and femoral arteries from either control or daunorubicin-treated animals. No relationship to the cumulative dose of the drug or post-expose set up of harvesting was found. In this study, we have demonstrated that daunorubicin does not induce gross histopathological changes in the studied arteries and it fails to induce immunohistochemically detectable endothelial dysfunction. Thus, we propose that endothelial cells are much less susceptible to anthracycline toxicity than cardiac myocytes. In addition, our data suggest that vascular toxicity of anthracyclines plays rather a minor role in the cardiovascular complications of anthracycline chemotherapy.
authors: Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Repubic. petr.nachtigal@faf.cuni.cz
authors: Petr
authors: P
authors: Nachtigal
authors: Martin
authors: M
authors: Sterba
authors: Olga
authors: O
authors: Popelová
authors: Lenka
authors: L
authors: Večeřová
authors: Zdenka
authors: Z
authors: Kudláčková
authors: Eduard
authors: E
authors: Jirkovský
authors: Vladimír
authors: V
authors: Geršl
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D017209:Apoptosis; D003630:Daunorubicin / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology*; D005263:Femoral Artery / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D019007:P-Selectin / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011817:Rabbits; D014652:Vascular Diseases / Q000139:chemically induced
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D019007:P-Selectin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003630:Daunorubicin