Protection by Hypoxia and the Effect of Low Oxygen Tensions on Radiosensitivity

It has been known for over 40 years that normal and malignant tissues which were poorly supplied with oxygen at the time of irradiation were less damaged by a given dose of X- or γ -rays than when well supplied with oxygen. Mottram, for example, in the mid 30’s suggested that the skin could be protected in radiotherapy by limiting the blood supply by pressure or other means during irradiation [1–3]. In 1942, Lacassagne demonstrated a marked protective effect of anoxia on lethality from whole-body irradiation by taking advantage of the fact that newborn mice are not killed by nitrogen asphyxia [4]. Studies on the relationship of radiosensitivity and oxygen were stimulated by Gray and his colleagues in 1953 in a paper which drew attention to the importance of oxygen supply in the treatment of tumours by radiotherapy. They pointed out that when radiosensitivity was plotted as a function of oxygen tension a ‘striking similarity in pattern’ of response for most systems was observed consisting of a rapid increase in sensitivity with increase in oxygen tension which gave way to a region in which radiosensitivity was almost unchanged by any further increase in oxygen concentration. On the basis of these observations they suggested that if anoxic foci did limit tumour response, improvement in the control of tumours in radiotherapy might be obtained by increasing the supply of oxygen to patients. The foci of tumour cells protected by hypoxia in normal conditions might then no longer be protected and thus the sensitivity of the tumour would be increased whilst normal tissues, which were usually well supplied with oxygen, would show no concomitant change in sensitivity [5]. Foci of cells are undoubtedly protected by hypoxia in tumours but whether these protected cells are the major cause of failure to control the primary growth in radiotherapy is still uncertain. Many hypoxic cells are likely to become reoxygenated during the course of fractionated treatments [6]. However, the most recent reports from clinical trials of hyperbaric oxygen at various centres throughout the world indicate that an improved local control is obtained by giving patients oxygen at 3 atmospheres pressure during irradiation compared with air breathing in patients given conventionally fractionated treatment [6, 7]. This does indicate that protection of tumour cells by hypoxia limits the effectiveness of radiotherapy and, in some cases, remains a problem throughout the course of fractionated treatment. This fact alone would make protection of cells by hypoxia an important study. However it has emerged from cell studies that oxygen reacts rapidly with the products of radiation and is closely implicated in both the fixing of damage and its repair. The study of the effects of hypoxia both during and after irradiation, the relationship of radiosensitivity and oxygen concentration and the factors affecting these must therefore form an important part of studies on the mechanism of radiation damage. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.