Abstract Body

Currently, radiation therapy (RT) is one of the most common methods of treating cancer. One of the primary challenges with RT is radiation toxicity and damage to healthy tissue surrounding the treatment area. Oxygen has been shown to provide an amplifying effect on the effectiveness of RT, when comparing RT delivery in normoxia relative to hypoxia. However, during FLASH delivery, Oxygen damage was significantly reduced as shown in many in-vitro and in-vivo studies.

The talk is divided into two main parts: (1) oxygen dynamics within the cell and across membranes and how this is affected by cholesterol content within a membrane, (ii) flash physico-chemical mechanisms currently published or being developed that try to provide an explanation to the FLASH effect.

In the first part of the talk, an overview is provided of how membrane structure and composition can alter the amount of oxygen that is available in nucleus at the time of irradiation. Recent biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. The amount of oxygen that can cross a membrane is therefore affect by the composition and structure of the lipid bilayer. We show that membranes that contain significant amount of cholesterol can significant reduce the oxygen diffusion across them and ultimately affect the amount of oxygen that reaches the nucleus. We also show that the structure of the membrane depends on the lipids present. For example, phosphatidylcholine accounts for >50% of the phospholipids in most eukaryotic membranes and are relatively transparent to oxygen diffusion across them. However, the sphingolipids constitute another class of structural lipids present in mammalian cells and are less permeable to oxygen. We also show that oxygen enhancement ratio (OER), is a parameter that ultimately depends on the ratio of the extra-cellular oxygen to nucleus, and therefore is a unique property of the cell.

In the second part of the talk, an overview is provided of the current published models on the FLASH mechanism. Special focus will be given to the molecular pathway model based on the fixation of R-radicals by oxygen (ROO) and on the redox model that proposed that FLASH effect depended on the difference in the scavenger capacity of cancer and health cells. We will also discuss a possible FLASH model developed in Heidelberg that focuses also on the difference in scavenging capacity of healthy tissues relative to cancer cells. The scavenging systems within different cell types is inherently different and can affect how each cell type responds to large amounts of radiation given in short pulses (FLASH). We will show how the FLASH effect can potentially be explained by the difference in the scavenging capacity of cancer cells relative to healthy cells. We will also discuss how oxygen affects the FLASH effect.