The proton accelerator at the Russian Academy of Sciences’ Institute for Nuclear Research provides a mode of irradiation of biological samples with a

The biological effects of proton irradiation with high and ultrahigh dose rates (up to 0.3 MGy/s) of cultured human tumor and normal cells at the Bragg pea

In order to study the FLASH effect using live models, this work compared proton-induced damage to embryos (nine days after fertilization) and one-day-old chicks (18 days after fertilization) from irradiated at different dose rates eggs of Japanese quail (Coturnix coturnix japónica). Eggs were irradiated with protons in different modes depending on the dose rate: in a conventional mode (<1 Gy/s, CONV), in a flash mode (∼100 Gy/s, FLASH) and in a single-pulse flash mode (∼10⁵ Gy/s SPLASH). By the criteria of body weight and length, as well as the number of erythrocytes with micronuclei in nine-day-old embryos from eggs irradiated in the spread-out Bragg peak (SOBP) (8.5 Gy), FLASH and SPLASH modes were found to be less traumatic compared with the CONV mode. Among all irradiated embryos, the maximum body weight and length were observed in the SPLASH mode. The lowest death incidence and the smallest number of abnormal erythrocytes were recorded after FLASH and SPLASH irradiation. In chicks that hatched from eggs irradiated in the CONV mode, a tendency for an increase in the number of abnormal erythrocytes was observed. The speed of movement of chicks from FLASH- and SPLASH-irradiated eggs was comparable with that from unirradiated eggs, while chicks from eggs irradiated in the CONV mode were less active than all others. The proton irradiation of eggs in SOBP using high dose-rate modes is less damaging for healthy tissues and for the development of embryos and chicks on the cellular, anatomical, and physiological levels.

Among the methods for increasing the specificity of tumor radiotherapy, FLASH radiotherapy (FLASH-RT) stands out, having recently entered clinical trials. A distinctive feature of this treatment method is the delivery of a therapeutic dose in a fraction of a second with a typical mean dose rate greater than 40 Gy/s. In addition to improved patient comfort and a shorter hospital stay, this therapy potentially carries a lower risk of radiation-related side effects due to reduced damage to normal tissues. Numerous preclinical and in vivo laboratory trials of FLASH-RT have demonstrated that, in addition to reducing the severity of radiation-related complications, FLASH radiotherapy has antitumor efficacy similar to conventional radiotherapy. Partly reduced radiotoxicity after such a dose rate delivery obtained, in a broader radiobiological sense, an eponymous term FLASH effect. Although the first clinical trials aimed to evaluate the safety and efficiency of FLASH-RT against bone metastases (FAST-01/02), melanoma skin metastases (IMPulse, Flash-Skin I), Squamous Cell Carcinoma, or Basal Cell Carcinoma (LANCE) have already started or even finished and showed promising results (FAST-01), the radiobiological basis of the FLASH effect is far from a complete explanation. The fundamental factors explaining the nature of the FLASH effect are mainly considered to be the following: (1) changes in the balance of water radiolysis products and a decrease in the generation of stable reactive oxygen species (ROS), (2) differential oxygen depletion, depending on the initial oxygen concentration in tissues, and (3) physiological and metabolic, gene expression and probably epigenetic shifts in response to irradiation in normal and tumor cells. The main purpose of this review is the systematization of the radiobiological manifestations of the FLASH effect together with a consideration of the elementary processes laying in the basis of the FLASH effect in order to actualize rationale and future application developments of FLASH-RT.

The study of biological effects of high-dose-rate ionizing radiation using animal models remains an urgent problem. In the work, a comparison of proton-induced damage to embryos (the 9 ^th post-fertilization day) and 1-day-old baby chicks (the 18 ^th post-fertilization day) from irradiated eggs of Japanese quail ( Coturnix coturnix japónica ) irradiated in and outside the Bragg peak with the conventional and ultra-high dose rate D (CONV D < 1 Gy/s, FLASH D ∼100 Gy/s and single-pulse flash - SPLASH D ∼10 ⁶ Gy/s, respectively) was carried out. The following criteria were used: survival, body weight and body length of embryos, weight of chicks, percentage of erythrocytes with anomalies (with micronuclei, without nuclei, with two nuclei), and the speed of movement of 1-day-old chicks in the open field test. The largest number of dead embryos was recorded after irradiation with 7 and 14 Gy in the plateau region of the proton trajectory. By the criteria of body weight and length, as well as the number of erythrocytes with micronuclei in 9-day-old embryos from eggs irradiated with a dose of 8.5 Gy in the Bragg peak, FLASH and SPLASH modes were found to be the least traumatic compared with the CONV mode. The weight of chicks from eggs irradiated with a dose of 4 Gy in the Bragg peak did not differ from the control and did not depend on the irradiation mode. The lowest death incidence and the smallest number of abnormal erythrocytes were recorded after FLASH and SPLASH irradiation; in chicks that hatched from eggs irradiated in the CONV mode, a tendency for an increase in the number of abnormal erythrocytes was observed. The speed of movement of chicks from FLASH- and SPLASH-irradiated eggs was comparable with that from unirradiated eggs, and chicks from eggs irradiated in the CONV mode were less active than chicks from unirradiated eggs and eggs irradiated in the other regimes. Thus, the irradiation of eggs with a beam of accelerated protons in the Bragg peak in the FLASH/SPLASH modes is less damaging for healthy tissues and for the development of embryos and chicks on the cellular, anatomical, and physiological levels.