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.

Doxorubicin-Induced Cardiotoxicity in Collaborative Cross (CC) Mice Recapitulates Individual Cardiotoxicity in Humans

“…A similar trend was seen for females of CC 019 and CC 042. Consistent with previously reported data across animal species (Bertinchant et al 2003; Desai et al 2013; Manno et al 2016), doxororubicin -treated animals demonstrated impaired growth over time compared to age matched vehicle treated controls. This varied by strain and sex.…”

Toxicity and Safety Evaluation of Doxorubicin-Loaded Cockleshell-Derived Calcium Carbonate Nanoparticle in Dogs

“…The changes in the blood cells especially erythrocytes, platelets, and leucocyte count were all DOX dose dependent and were consistent with the findings reported by Manno et al [ 5 ]; Tacar et al [ 51 ], which could be attributed to the known bone marrow suppressive effect of DOX and iron-DOX interaction, thus causing RBC membrane rupture as previously reported by Vici et al [ 52 ] and Pahouja et al [ 53 ] since DOX did not limit its effects not only to cancer cell alone but also to proliferating haematopoietic cells.…”

“…However, the carrier molecules are entrapped within the slit diaphragm due to the size of the carrier molecules used in drug delivery leading to renal tubular tissue injury [ 82 ]. The glomerular and tubular damage observed in our study was similar to the lesion seen in rodent as reported by Cianciolo et al [ 83 ] and Manno et al [ 5 ] in rodent and mini pig animal models, respectively. In addition, our results also agree with the works of Anan et al [ 84 ] as clusters of nuclear material were observed as a result of free radical production from lipid peroxidation.…”

“…Doxorubicin (DOX) is one of the potent chemotherapeutic agents used in the management of both haematopoietic and solid malignant tumours of different origin [ 1 – 3 ]. In the past two decades, its application by oncologists has been extensively explored, although its continuous usage alone in clinical settings is impeded due to its life-threatening effect on organs such as heart, kidney, and liver [ 4 , 5 ]. DOX toxicity is generally inclined to the mitochondrial oxidative phosphorylation and calcium ion overload through multiple complex pathways [ 2 , 6 ].…”

A genetically inducible porcine model of intestinal cancer

“…To augment studies in mice, new animal models of cancer are needed. The pig is a promising alternative model organism due to its high degree of similarity to humans, including longevity, size, organ anatomy, physiology, drug metabolism, genetics, and immunology (Flisikowska et al, 2013;Forster et al, 2010;Kuzmuk and Schook, 2011;Manno et al, 2016;Mote and Rothschild, 2006;Wernersson et al, 2005). Importantly, the large size of pigs also brings opportunities for longitudinal sampling and therefore monitoring of tumor evolution during treatment, which is generally not possible in rodents.…”