Effects of local irradiation combined with sunitinib on early remodeling, mitochondria, and oxidative stress in the rat heart

Background and purpose: Thoracic (chemo)radiation therapy is increasingly administered with tyrosine kinase inhibitors (TKI). While TKI have adverse effects on the heart, it is unknown whether combination with other cancer therapies causes enhanced toxicity. We used an animal model to investigate whether radiation and sunitinib interact in their effects on the heart. Material and methods: Male Sprague-Dawley rats received local heart irradiation (9 Gy per day, 5 days). Oral sunitinib (8 or 15 mg/kg bodyweight per day) started on day 1 of irradiation and continued for 2 weeks. Cardiac function was examined with echocardiography. Cardiac remodeling, cell death, left ventricular (LV) oxidative stress markers, mitochondrial morphology and mitochondrial permeability transition pore (mPTP) opening were assessed. Results: Cardiac diameter, stroke volume, and LV volume, mass and anterior wall thickness increased in time, but only in the vehicle group. Sunitinib reduced LV inner diameter and volume in systole, which were counteracted by radiation. Sunitinib and radiation showed enhanced effects on mitochondrial morphology and mPTP opening, but not on cardiac troponin I, mast cell numbers or markers of oxidative stress. Conclusions: This study found no early enhanced effects of radiation and sunitinib on cardiac function or structure. Long-term effects remain to be determined. (C) 2016 Elsevier Ireland Ltd. All rights reserved.