Multicellular Spheroids as In Vitro Models of Oxygen Depletion During FLASH Irradiation
| Autor: | Maxime Bassenne, Peter G. Maxim, Rakesh Manjappa, Jinghui Wang, Lei Xing, Guillem Pratx, Billy W. Loo, Dylan Y. Breitkreutz, Stavros Melemenidis, Syamantak Khan |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
genetic structures Lipoproteins chemistry.chemical_element Models Biological Oxygen 030218 nuclear medicine & medical imaging 03 medical and health sciences Flash (photography) 0302 clinical medicine Spheroids Cellular Radioresistance Fluorescence microscope Humans Medicine Radiology Nuclear Medicine and imaging Viability assay Irradiation Radiation business.industry Spheroid Oncology chemistry 030220 oncology & carcinogenesis embryonic structures Oxygen enhancement ratio Biophysics business |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 110:833-844 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2021.01.050 |
| Popis: | Purpose The differential response of normal and tumor tissues to ultrahigh-dose-rate radiation (FLASH) has raised new hope for treating solid tumors but, to date, the mechanism remains elusive. One leading hypothesis is that FLASH radiochemically depletes oxygen from irradiated tissues faster than it is replenished through diffusion. The purpose of this study was to investigate these effects within hypoxic multicellular tumor spheroids through simulations and experiments. Methods and Materials Physicobiological equations were derived to model (1) the diffusion and metabolism of oxygen within spheroids; (2) its depletion through reactions involving radiation-induced radicals; and (3) the increase in radioresistance of spheroids, modeled according to the classical oxygen enhancement ratio and linear-quadratic response. These predictions were then tested experimentally in A549 spheroids exposed to electron irradiation at conventional (0.075 Gy/s) or FLASH (90 Gy/s) dose rates. Clonogenic survival, cell viability, and spheroid growth were scored postradiation. Clonogenic survival of 2 other cell lines was also investigated. Results The existence of a hypoxic core in unirradiated tumor spheroids is predicted by simulations and visualized by fluorescence microscopy. Upon FLASH irradiation, this hypoxic core transiently expands, engulfing a large number of well-oxygenated cells. In contrast, oxygen is steadily replenished during slower conventional irradiation. Experimentally, clonogenic survival was around 3-fold higher in FLASH-irradiated spheroids compared with conventional irradiation, but no significant difference was observed for well-oxygenated 2-dimensional cultured cells. This differential survival is consistent with the predictions of the computational model. FLASH irradiation of spheroids resulted in a dose-modifying factor of around 1.3 for doses above 10 Gy. Conclusions Tumor spheroids can be used as a model to study FLASH irradiation in vitro. The improved survival of tumor spheroids receiving FLASH radiation confirms that ultrafast radiochemical oxygen depletion and its slow replenishment are critical components of the FLASH effect. |
| Databáze: | OpenAIRE |
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