Abstract
Radiation therapy in the treatment of cancer is dose limited by radiation injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-β1) in intestinal and cardiac radiation injury, we studied the influence of pharmacological induction of TGF-β1 with xaliproden (SR 57746A) in rat models of radiation enteropathy and radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-β induction may enhance radiation injury in heart and intestine, animals were exposed to irradiation schedules that cause mild to moderate (acute) radiation injury. In the radiation enteropathy model, male Sprague-Dawley rats received local irradiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal injury was assessed at 2 weeks and 12 weeks after irradiation. In the RIHD model, male Sprague-Dawley rats received local heart irradiation with a single dose of 18 Gy and were followed for 6 months after irradiation. Rats were treated orally with xaliproden starting 3 days before irradiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-β1 levels by 300% and significantly induced expression of TGF-β1 and TGF-β1 target genes in the irradiated intestine and heart. Various radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-β1 induction. Similarly, in the RIHD model induction of TGF-β1 augmented radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-β1 in biological mechanisms of radiation-induced adverse remodeling in the intestine and the heart.
Highlights
At least 50 percent of all cancer patients will receive radiotherapy at some stage of their cancer treatment
To identify the role of transforming growth factor-beta 1 (TGF-b1) in intestinal and cardiac radiation injury, we studied the influence of its induction with xaliproden in rat models of radiation enteropathy and Radiation-induced heart disease (RIHD)
The increase in TGF-b1 levels seemed to occur only in the plasma, as TGF-b1 protein did not change in skeletal muscle, cardiac left ventricle, cardiac atria, liver, kidney or small intestine
Summary
At least 50 percent of all cancer patients will receive radiotherapy at some stage of their cancer treatment. The intestine and the heart are dose-limiting organs in radiotherapy of the abdomen and the chest, respectively. Radiotherapy of abdominal and pelvic malignancies may lead to acute and chronic radiation enteropathy. Chronic radiation enteropathy may develop several years after radiotherapy and is characterized by progressive intestinal wall fibrosis and vascular sclerosis [1,2]. Radiation-induced heart disease (RIHD) may present several years after radiotherapy of intrathoracic and chest wall tumors and involves accelerated atherosclerosis, conduction defects, and/or myocardial fibrosis [3,4,5]. Even though radiotherapy has been greatly improved over the last decades, radiation injury in organs such as the heart and intestine still limits the dose that can be delivered to the target. Research is needed to identify biological mechanisms that underlie these toxicities
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