Abstract
The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. Cancer Res; 77(22); 6389-99. ©2017 AACR.
Highlights
The discovery of the radiation-induced bystander effect (RIBE; ref. 1) has expanded knowledge of radiobiological mechanisms beyond the scope of the central dogma of radiation biology, i.e., only cells that absorbed a dose of ionizing radiation (IR) are affected and the response is dose-dependent
microbeam radiotherapy (MRT) and BB irradiations of skin patches induced a wide range of persistent systemic effects in irradiated mice
These effects resulted even from a very short pulse (200 ms for 10-Gy peak dose; 810 ms for 40-Gy peak dose irradiations) of the irradiated area that was as small as 0.5 mm2, compared with approximately 80 cm2 body surface area of a 25 g mouse
Summary
The discovery of the radiation-induced bystander effect (RIBE; ref. 1) has expanded knowledge of radiobiological mechanisms beyond the scope of the central dogma of radiation biology, i.e., only cells that absorbed a dose of ionizing radiation (IR) are affected and the response is dose-dependent. The discovery of the radiation-induced bystander effect There are studies demonstrating that radiotherapy may exert an abscopal effect in improving the therapeutic response of tumors outside the radiation field, raising the possibility of suppressing tumorigenesis at distant sites [4, 8]. These observations of nontargeted effects that accompany radiotherapy, which is part of the treatment for www.aacrjournals.org about half of all cancer patients [9], prompt consideration of these effects in treatment planning [1]
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