A Radiation Biological Analysis of the Oxygen Effect as a Possible Mechanism in FLASH

The delivery of radiation at an ultra-high dose rate (FLASH) is an important new approach to radiotherapy (RT) that appears to be able to improve the therapeutic ratio by diminishing damage to normal tissues. While the mechanisms by which FLASH improves outcomes have not been established, a role involving molecular oxygen (O₂) is frequently mentioned. In order to effectively determine if the protective effect of FLASH RT occurs via a differential direct depletion of O₂ (compared to conventional radiation), it is essential to consider the known role of O₂ in modifying the response of cells and tissues to ionising radiation (known as 'the oxygen effect'). Considerations include: (1) The pertinent reaction involves an unstable intermediate of radiation-damaged DNA, which either undergoes chemical repair to restore the DNA or reacts with O₂, resulting in an unrepairable lesion in the DNA, (2) These reactions occur in the nuclear DNA, which can be used to estimate the distance needed for O₂ to diffuse through the cell to reach the intermediates, (3) The longest lifetime that the reactive site of the DNA is available to react with O₂ is 1-10 μsec, (4) Using these lifetime estimates and known diffusion rates in different cell media, the maximal distance that O₂ could travel in the cytosol to reach the site of the DNA (i.e., the nucleus) in time to react are 60-185 nm. This calculation defines the volume of oxygen that is pertinent for the direct oxygen effect, (5) Therefore, direct measurements of oxygen to determine if FLASH RT operates through differential radiochemical depletion of oxygen will require the ability to measure oxygen selectively in a sphere of <200 nm, with a time resolution of the duration of the delivery of FLASH, (6) It also is possible that alterations of oxygen levels by FLASH could occur more indirectly by affecting oxygen-dependent cell signalling and/or cellular repair.