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

Abstract

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 membrane 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.

Effects of ionizing radiation on the heart

“…Radiation-induced heart disease in animal models appears to be associated with long-term oxidative stress [36;43;46]. Hence, some of the interventions that have been tested in animal models of radiation-induced heart disease act via anti-oxidant mechanisms.…”

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…However, due to the time and cost required for image-guided radiation therapy and potential anesthesia requirements of daily fractionated treatments, it may be difficult to model multi-week treatments using small fractions similar to commonly used clinical regimens (i.e., 1.8-2.7 Gy daily). Thus, a number of studies utilize larger daily fractions for more limited time periods, such as cardiac exposures to 9 Gy for five daily treatments [49,169].…”

“…The cardiac effects of the combination of radiation with other anti-cancer agents are less commonly studied. For instance, while whole heart x-rays in combination with a tyrosine kinase inhibitor in rats may have more severe effects on cardiac mitochondrial structure than each of the treatments alone, long-term effects on cardiac function with these therapies are not yet known [169]. As more and more patients receive multiple and more diverse personalized therapies, further studies need to be conducted to study how multiple therapies interact to cause short-and long-term cardiovascular effects.…”

Acquired Immunity Is Not Essential for Radiation-Induced Heart Dysfunction but Exerts a Complex Impact on Injury

“…Furthermore, many cancer patients who receive RT also receive systemic therapies such as chemotherapy. While there were studies to investigate the effects of combining cardiac RT and chemotherapeutic agents such as doxorubicin [68][69][70] and sunitinib [48], the cardiac effects of the combination of radiation and immunotherapies are less studied [66,67]. Because many immunotherapies target the mechanisms that restrain T cells to enhance tumor immunity, such as blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with ipilimumab [71] or programmed death protein 1 (PD-1) with pembrolizumab [72], these approaches could adversely impact normal cardiac tissue [66,67,71,72].…”

“…We subsequently expanded our study to a more clinically relevant fractionated RT dose, using an image-guided localized cardiac RT regimen of 9 Gy × 5 daily fractions [26,[46][47][48]. This regimen was previously shown to cause RIHD in the SS WT rats [26].…”