Abstract
ObjectiveSynchrotron radiation has shown high therapeutic potential in small animal models of malignant brain tumours. However, more studies are needed to understand the radiobiological effects caused by the delivery of high doses of spatially fractionated x-rays in tissue. The purpose of this study was to explore the use of the γ-H2AX antibody as a marker for dose deposition in the brain of rats after synchrotron microbeam radiation therapy (MRT).MethodsNormal and tumour-bearing Wistar rats were exposed to 35, 70 or 350 Gy of MRT to their right cerebral hemisphere. The brains were extracted either at 4 or 8 hours after irradiation and immediately placed in formalin. Sections of paraffin-embedded tissue were incubated with anti γ-H2AX primary antibody.ResultsWhile the presence of the C6 glioma does not seem to modulate the formation of γ-H2AX in normal tissue, the irradiation dose and the recovery versus time are the most important factors affecting the development of γ-H2AX foci. Our results also suggest that doses of 350 Gy can trigger the release of bystander signals that significantly amplify the DNA damage caused by radiation and that the γ-H2AX biomarker does not only represent DNA damage produced by radiation, but also damage caused by bystander effects.ConclusionIn conclusion, we suggest that the γ-H2AX foci should be used as biomarker for targeted and non-targeted DNA damage after synchrotron radiation rather than a tool to measure the actual physical doses.
Highlights
Conventional radiotherapy has been very successful at treating a wide variety of cancers such as those of skin and breast, but it still remains poorly effective when targeting malignant brain tumours
We suggest that the γ-H2AX foci should be used as biomarker for targeted and non-targeted DNA damage after synchrotron radiation rather than a tool to measure the actual physical doses
We analyzed the brain of Wistar rats after three different doses of synchrotron radiation (35, 75, and 350 Gy) using either microbeams or broad beams
Summary
Conventional radiotherapy has been very successful at treating a wide variety of cancers such as those of skin and breast, but it still remains poorly effective when targeting malignant brain tumours. The most frequent tumours—glioblastoma multiforme (GBM) in adults, and astrocytic tumours in children—are both the most aggressive and resistant to radiation therapy [2,3]. Research on microbeam radiation therapy (MRT) in the last two decades, initiated at the National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory (BNL), Upton, New York, was continued at the European Synchrotron Radiation Facility (ESRF) and at other international facilities. The remarkable sparing by x-ray microbeams of normal tissues of vertebrates— of the normal brain and spinal cord—has been extensively documented in suckling and adult rats [5,9,10,11,12,13,14,15], duck embryos [16], and weanling piglets [17]. MRT-associated bystander effects have been identified [20,21,22], and gene expression analysis of intracerebral gliosarcomas in rats have identified MRT-induced immune modulations [23] and cytostatic effects [24]
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