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Evaluating novel compounds for mimicking the FLASH effect in-vitro by using Conventional Irradiation
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Resumo(s)
The present in vitro study investigated the possibility to mimic the FLASH effect focusing on the antioxidant response mechanisms involved in the radical production. The primary interest was directed towards the superoxide anion, removed by intracellular superoxide dismutase-1 (SOD1), therefore being the target of the study. Two different copper-chelating compounds, ATN-224 and TETA-4, were used to inhibit the enzymatic activity of SOD1, in one head&neck cancer cell line, SAS, and in a skin healthy cell line, HaCaT. The optimal concentration for cell treatment was established by optimizing parameters including cell viability and SOD1 inhibition. Radiation experiments were performed using X-rays in conventional mode, and electrons in both conventional and FLASH mode, applied to untreated and drugtreated cells. Two distinct electron beams were used for the study, one at the University of Antwerp and one at the ELBE facility in Dresden. The clonogenic cell survival, SOD activity and GSH/GSSG ratio were investigated. ATN-224 inhibited SOD1 enzymatic activity, while for TETA-4 this result was not observable. At conventional dose rates, copper chelation alone did not improve cell radio-resistance and effective SOD1 inhibition was required. In HaCaT cells under FLASH irradiation, increased cell survival was observed, as well as SOD activity 72 hours after irradiation. In SAS cells, cell survival remained unchanged, and only a slight increase in SOD activity was noticed 72 hours after irradiation. The combination of FLASH with ATN-224 did not amplify the radioprotective effect in healthy cells, while exhibited a dose-dependent increase in cancer cells. Measurements of the GSH/GSSG ratio 72 hours after irradiation were inconclusive. For the electron beam at ELBE, healthy cell survival remained approximately constant in both dose rate regimes, for untreated and ATN-224-treated cells prior to irradiation. When irradiated in FLASH mode in the presence of TETA-4, cell survival did not significantly change.
Descrição
Tese de mestrado, Engenharia Biomédica e Biofísica, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
FLASH effect Superoxide dismutase-1 (SOD1) superoxide anion ROS