Pre-Clinical Radiobiological Studies of Murine Brain and Brain Cancer Cells to Synchrotron X-rays and Gamma Irradiation

Abstract

This thesis demonstrates the relevance of bystander effect mechanisms after exposure to two Synchrotron modalities – Microbeam Radiation Therapy and Pencilbeam – that are currently at the preclinical stage but aim to treat brain tumours. We elucidate the relationship between the hyper-radiosensitivity phenomenon and radiation-induced bystander effects by studying the dose response of three glioma cell lines. The relevance of these low-dose effects for both Synchrotron modalities is because the tissue exposed to low valley-doses is predicted to be where hyper-radiosensitivity and bystander effects might be expected to predominate. In vivo experiments were conducted in the European Synchrotron radiation Facility in Grenoble, France and also in the University of Freiburg’s Hospital in Freiburg, Germany. Experiments conducted in vitro were performed at McMaster University. The most relevant results of this thesis revealed that the low-dose hyper-radiosensitivity phenomenon can coexist with radiation-induced bystander effects and evidence points towards bystander signalling mechanisms as the primary cause of cell killing during hyper-radiosensitivity. Bystander and abscopal effects can occur in rats and even in immune-compromised nude mice after exposure to Synchrotron Microbeam Radiation and Pencilbeam. Bystander effects can be communicated from irradiated rats to healthy unirradiated cage mate rats and the presence of a tumour modulates both the bystander and abscopal responses. The γ-H2AX biomarker can successfully be used for the detection of DNA damage in the brain of rodents after Synchrotron Radiation. In conclusion, this thesis considerably expands the understanding of the role of bystander effects in cells lines, tissues, and animals exposed to Synchrotron radiation. It is suggested that further exploration of the role of bystander effects and hyper-radiosensitivity during Synchrotron treatments could identify new targets leading to better tumour control.