Potential of FLASH irradiation to minimize the incidence of radio-induced damage and fibrosis to normal lung in a mouse model

Submillisecond pulses of radiation have been shown to generate less exchange chromosomal aberrations [1, 2] and a smaller extent of delayed cell death [3, 4] than continuous irradiation delivered at conventional dose-rate. This prompted us to determine whether and how pulsed irradiation affects the response of normal lung tissue in vivo. For this purpose, C57BL/ 6J mice were given a single dose of 17 Gy of 4.5 MeV electrons in bilateral thorax exposure either at a high (> 60 Gy/s, beam-on time < 0.5 s, FLASH) or conventional dose-rate (0.03 Gy/s, beam-on time 8 min, CONV) using an experimental linear electron accelerator established in the Research Division of Institut Curie at Orsay (France). DNA damage response, apoptosis and fibrosis development were subsequently analyzed at suitable times in the two modes of irradiation. The anti-tumor efficiency was also evaluated in vivo with two xenografts (HBCx12A, HEp-2) and one syngeneic, orthotopic carcinoma (TC1-Luc). The results indicate that, in the hours following irradiation, FLASH-irradiated lungs present less DNA damages and less apoptosis than lungs irradiated at a conventional dose-rate. Furthermore, compared to the classical radiation-induced lung fibrosis observed past 16-weeks after CONV irradiation, analysis of FLASH-treated lungs did not show any histological sign of fibrosis nor activation of the TGF-beta pathway. However, FLASH irradiation was as efficient as CONV treatment in controlling tumor growth. Taken together, these results show that FLASH irradiation selectively spares normal lung tissue without any loss of the anti-tumor activity [5].