Audrey Bouchet1, Elke Bräuer-Krisch2, Yolanda Prezado2, Michèle El Atifi3, Léonid Rogalev2, Céline Le Clec'h2, Jean Albert Laissue4, Laurent Pelletier5, Géraldine Le Duc2. 1. Université Grenoble Alpes, Grenoble Institut des Neurosciences, Grenoble, France; Biomedical Beamline, European Synchrotron Radiation Facility, Grenoble, France. Electronic address: audrey.m.bouchet@gmail.com. 2. Biomedical Beamline, European Synchrotron Radiation Facility, Grenoble, France. 3. Université Grenoble Alpes, Grenoble Institut des Neurosciences, Grenoble, France; Grenoble University Hospital, Grenoble, France. 4. University of Bern, Bern, Switzerland. 5. Université Grenoble Alpes, Grenoble Institut des Neurosciences, Grenoble, France; Grenoble University Hospital, Grenoble, France. Electronic address: laurent.pelletier@ujf-grenoble.fr.
Abstract
PURPOSE: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood. METHODS AND MATERIALS: Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control and on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis. RESULTS: MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P<.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT. CONCLUSIONS: These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses.
PURPOSE: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood. METHODS AND MATERIALS: Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control and on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis. RESULTS: MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P<.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT. CONCLUSIONS: These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses.
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