Giuseppina Milano1, Angela Raucci2, Alessandro Scopece2, Ranaldi Daniele2, Uliano Guerrini3, Luigi Sironi4, Daniela Cardinale5, Maurizio C Capogrossi6, Giulio Pompilio7. 1. Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy. Electronic address: giuseppina.milano@ccfm.it. 2. Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy. 3. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. 4. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Unit of Experimental Thrombosis and Imaging in Vivo, Centro Cardiologico Monzino - IRCCS, Milan, Italy. 5. Cardioncology Unit, European Institute of Oncology, Milan, Italy. 6. Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata - IRCCS, Rome, Italy. 7. Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy; Department of Clinical and Community Sciences, University of Milan, Milan, Italy.
Abstract
BACKGROUND: An increased risk for cardiac dysfunction is reported when the anti-epidermal growth factor receptor type 2 (ErbB2) antibody trastuzumab (Trz) is combined with doxorubicin (Dox) as adjuvant chemotherapy for patients with ErbB2-positive breast cancer. The aim of this study was to develop and characterize a novel mouse model of cardiotoxicity that recapitulates the clinical therapeutic protocols of consecutive cycles of Dox followed by Trz therapy. METHODS: Chronic cardiotoxicity was induced in mice by administering six intraperitoneal injections of Dox weekly over a 2-week period (n = 38; cumulative dose, 24 mg/kg), Trz alone (n = 15; cumulative dose, 10 mg/kg), Trz administered 1 week after Dox treatment (n = 35), or an equivalent volume of saline (n = 24). RESULTS: Echocardiography and pressure-volume analysis indicated that Dox administration was responsible for both left ventricular (LV) and right ventricular (RV) systolic dysfunction and dilatation, further exacerbated by subsequent Trz treatment. Trz alone induced a short down-regulation of LV ErbB2/4 expression associated with reversible LV dysfunction but did not affect receptor expression and RV performance. Dox and Trz in combination decreased the ratio of LV weight to tibia length as well as LV and RV wall thickness compared with Dox treatment. Plasma cardiac troponin I levels and myocardial oxidative stress were higher in mice treated with Dox and Trz than in those treated with Dox alone, while a similar increase of interstitial collagen I deposition was observed in both groups. Trz alone did not affect LV and RV remodeling. CONCLUSIONS: These findings suggest that a combined Dox and Trz regimen provokes a detrimental synergistic global cardiac injury extending to both the LV and RV chambers.
BACKGROUND: An increased risk for cardiac dysfunction is reported when the anti-epidermal growth factor receptor type 2 (ErbB2) antibody trastuzumab (Trz) is combined with doxorubicin (Dox) as adjuvant chemotherapy for patients with ErbB2-positive breast cancer. The aim of this study was to develop and characterize a novel mouse model of cardiotoxicity that recapitulates the clinical therapeutic protocols of consecutive cycles of Dox followed by Trz therapy. METHODS: Chronic cardiotoxicity was induced in mice by administering six intraperitoneal injections of Dox weekly over a 2-week period (n = 38; cumulative dose, 24 mg/kg), Trz alone (n = 15; cumulative dose, 10 mg/kg), Trz administered 1 week after Dox treatment (n = 35), or an equivalent volume of saline (n = 24). RESULTS: Echocardiography and pressure-volume analysis indicated that Dox administration was responsible for both left ventricular (LV) and right ventricular (RV) systolic dysfunction and dilatation, further exacerbated by subsequent Trz treatment. Trz alone induced a short down-regulation of LV ErbB2/4 expression associated with reversible LV dysfunction but did not affect receptor expression and RV performance. Dox and Trz in combination decreased the ratio of LV weight to tibia length as well as LV and RV wall thickness compared with Dox treatment. Plasma cardiac troponin I levels and myocardial oxidative stress were higher in mice treated with Dox and Trz than in those treated with Dox alone, while a similar increase of interstitial collagen I deposition was observed in both groups. Trz alone did not affect LV and RV remodeling. CONCLUSIONS: These findings suggest that a combined Dox and Trz regimen provokes a detrimental synergistic global cardiac injury extending to both the LV and RV chambers.
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