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Ultra-High Dose Rate FLASH Irradiation Induced Radio-Resistance of Normal Fibroblast Cells Can Be Enhanced by Hypoxia and Mitochondrial Dysfunction Resulting From Loss of Cytochrome C.

ABSTRACT: Ultra-high dose rate FLASH irradiation (FLASH-IR) has got extensive attention since it may provide better protection on normal tissues while maintain tumor killing effect compared with conventional dose rate irradiation. The FLASH-IR induced protection effect on normal tissues is exhibited as radio-resistance of the irradiated normal cells, and is suggested to be related to oxygen depletion. However, the detailed cell death profile and pathways are still unclear. Presently normal mouse embryonic fibroblast cells were FLASH irradiated (∼10⁹ Gy/s) at the dose of ∼10-40 Gy in hypoxic and normoxic condition, with ultra-fast laser-generated particles. The early apoptosis, late apoptosis and necrosis of cells were detected and analyzed at 6, 12, and 24 h post FLASH-IR. The results showed that FLASH-IR induced significant early apoptosis, late apoptosis and necrosis in normal fibroblast cells, and the apoptosis level increased with time, in either hypoxic or normoxic conditions. In addition, the proportion of early apoptosis, late apoptosis and necrosis were significantly lower in hypoxia than that of normoxia, indicating that radio-resistance of normal fibroblast cells under FLASH-IR can be enhanced by hypoxia. To further investigate the apoptosis related profile and potential pathways, mitochondria dysfunction cells resulting from loss of cytochrome c (cyt c^-/-) were also irradiated. The results showed that compared with irradiated normal cells (cyt c^+/+), the late apoptosis and necrosis but not early apoptosis proportions of irradiated cyt c^-/- cells were significant decreased in both hypoxia and normoxia, indicating mitochondrial dysfunction increased radio-resistance of FLASH irradiated cells. Taken together, to our limited knowledge, this is the first report shedding light on the death profile and pathway of normal and cyt c^-/- cells under FLASH-IR in hypoxic and normoxic circumstances, which might help us improve the understanding of the FLASH-IR induced protection effect in normal cells, and thus might potentially help to optimize the future clinical FLASH treatment.

SUBMITTER: Han J

PROVIDER: S-EPMC8121317 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1-3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible.

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Ultra-High Dose Rate FLASH Irradiation Induced Radio-Resistance of Normal Fibroblast Cells Can Be Enhanced by Hypoxia and Mitochondrial Dysfunction Resulting From Loss of Cytochrome C.

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