title: The minipig as a new model for the evaluation of doxorubicin-induced chronic toxicity.
abstract: Doxorubicin can cause life-threatening toxic effects in several organs, with cardiotoxicity being the major concern. Although a large number of animal models have been utilized to study doxorubicin toxicity, several restrictions limit their use. Since the Göttingen minipig is an accepted species for non-clinical safety assessment and translation to man, we aimed at exploring its use as a non-rodent animal model for safety assessment and regulatory toxicity studies using doxorubicin. Three groups of three males and three females adult Göttingen minipigs received 1.5 mg kg(-1) , 3/2.3 mg kg(-1) or vehicle at intervals of 3 weeks for 7 cycles. Doxorubicin treatment resulted in a dose-related decrease in the erythrocytes, hemoglobin and hematocrit count, accompanied by leukopenia and thrombocytopenia. Bone marrow smears revealed dose-related hypocellularity. Urea and creatinine levels were elevated in treated animals, associated with proteinuria and hematuria. Histopathological evaluation detected nephropathy and atrophy of hematopoietic tissues/organs, mucosa of the intestinal tract and male genital tract. Cardiac lesions including chronic inflammation, endocardial hyperplasia, hemorrhage and myxomatous changes were evident in hematoxylin and eosin stains, and evaluation of semi-thin sections showed the presence of dose-related vacuolation in the atrial and ventricular cardiomyocytes. Cardiac troponin levels were increased in the high-dose group, but there was no direct correlation to the severity of the histopathological lesions. This study confirms that the Göttingen minipig has a comparable toxicity profile to humans and considering its anatomical, physiological, genetic and biochemical resemblance to humans, it should be considered as the non-rodent species of choice for studies on doxorubicin toxicity. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, Research Toxicology Centre, Pomezia, Italy.
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Manno
authors.affiliation: Department of Pathology, Research Toxicology Centre, Pomezia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Grassetti
authors.affiliation: Scientific Director, Research Toxicology Centre, Pomezia, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Oberto
authors.affiliation: Department of Pathology, Sackler School of Medicine, University of Tel Aviv, and Consultant in Toxicologic Pathology, Timrat, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.affiliation: Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ramot
mesh_terms: D000818:Animals; D001835:Body Weight; D066126:Cardiotoxicity / Q000175:diagnosis / Q000209:etiology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D004562:Electrocardiography; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005835:Genitalia / Q000187:drug effects / Q000378:metabolism; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D006965:Hyperplasia / Q000139:chemically induced / Q000175:diagnosis; D007674:Kidney Diseases / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D008689:Methacrylates / Q000633:toxicity; D013552:Swine; D013556:Swine, Miniature; D036401:Toxicity Tests, Chronic; D014336:Troponin / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D008689:Methacrylates; D014336:Troponin; C005044:hydroxyethyl methacrylate; D004317:Doxorubicin
keywords: animal model; cardiotoxicity; doxorubicin; minipig; safety assessment