Over successive decades, rigorous scientific research was conducted to facilitate the continuous advancements in knowledge of the fundamental mechanisms of action and factors affecting radiosensitivity. The origins of radiotherapy date back to 1896 when Emil Herman Grubbé utilised X-rays, less than 60 days after their discovery by Wilhelm Conrad Röntgen, to treat a case of advanced ulcerative breast cancer in Chicago with little knowledge of their physical properties or biological effects. However, translating the original findings of Thomlinson and Gray remains a research priority with the potential to significantly improve patient outcomes and specifically those receiving radiotherapy. Significant contributing factors underpinning disappointing clinical trial results include the use of model systems which are more hypoxic than human tumours and a failure to stratify patients based on levels of hypoxia. However, despite an abundance of pre-clinical data supporting hypoxia-targeted treatments, there is limited widespread application of hypoxia-targeted therapies routinely used in clinical practice. Furthermore, this subsequently resulted in investigations into markers and measurement of hypoxia, as well as modification strategies. Ultimately, the work pioneered by Thomlinson and Gray led to numerous elegant studies which demonstrated that tumour hypoxia predicts for poor patient outcomes. By proving that tumours have large necrotic cores due to hypoxia and that hypoxic cells require significantly larger doses of ionising radiation to achieve the same cell kill, Thomlinson and Gray inspired the subsequent decades of research into better defining the mechanistic role of molecular oxygen at the time of radiation. Pivotal research led by Louis Harold Gray in the 1950s suggested that oxygen plays a vital role during radiotherapy.
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