Main Session
Sep 29
SS 21 - Radiation and Cancer Biology 3: Normal Tissue Injury & Biomarkers

225 - The Critical Role of Instantaneous Dose Rate in Mitigating Lethality and Radiation-Induced Toxicities in Murine Total-Body Irradiation: A Comparative Analysis of Dose Rate Regimens

11:05am - 11:15am PT
Room 153

Presenter(s)

Hongyu Zhu, PhD - Sun Yat-Sen University Cancer Center, Guang Dong Province, Guangdong

H. Zhu1, S. Liu2, J. Qiu3, A. Hu4, W. Zhou4, J. Wang3, W. Gu4, H. Zha5, R. Xiang2, J. Li4, R. Qiu4, C. Zhao2, P. Huang2, and X. W. Deng2; 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, Guangzhou, China, 2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, Gangzhou, China, 3Beijing Huaqingjia High Energy Electron Technology Corporation Limited, Beijing, China, 4Department of Engineering Physics, Tsinghua University, Beijing, China, 5Key Laboratory of Particle and Radiation Imaging of Ministry of Education, Tsinghua University, Beijing, China

Purpose/Objective(s): Ultra-high dose rate (UHDR) irradiation holds promise for tumor control while minimizing normal tissue toxicities. However, its biological effects depend on multiple parameters, particularly the mean and instantaneous dose rates. Furthermore, limited data exist on UHDR effects in large-field irradiation. This study investigates the impact of different dose rate combinations on hematopoietic and gastrointestinal toxicity and molecular responses following total-body irradiation (TBI).

Materials/Methods: Three TBI protocols (10 Gy) were administered to female C57BL6/J mice: 1) Combined ultra-high mean/instantaneous dose rate (HH), 2) Low mean/ultra-high instantaneous dose rate (LH), and 3) Low mean/instantaneous dose rate (LL). Mice were sacrificed at 3 h and 48 h post-irradiation for acute tissue damage assessment and transcriptome sequencing. Survival was monitored for 30 days.

Results: Instantaneous dose rates exceeding 105 Gy/s (HH/LH groups) demonstrated comparable survival advantages over LL irradiation (30-day survival: HH=57.1%, LH=66.7%, LL=0%). Both HH and LH protocols exhibited marked attenuation in hematopoietic suppression (3h/48h post-TBI), diminished ?-H2AX foci formation, and reduced intestinal apoptosis versus LL irradiation. Inflammatory regulation improved significantly in HH/LH groups by 48h. Transcriptomic analysis revealed HH irradiation uniquely activated immune modulation pathways while downregulating mitochondrial pathways compared to LL controls.

Conclusion: Instantaneous dose rate plays a decisive role in mitigating radiation-induced damage. When sufficiently high (>105 Gy/s), it confers radioprotective effects regardless of mean dose rate, highlighting its critical importance in optimizing UHDR radiotherapy strategies. These findings advance the mechanistic understanding of UHDR radiobiology and provide essential parameters for optimizing therapeutic ratio in extended-field radiotherapy applications.

Abstract 225 - Table 1: Irradiation parameters and outcomes of three TBI protocols

(1) Mean ± standard deviation (SD)

* p<0.05 compared with HH mode

# p<0.05 compared with LH mode
Unit

 HH mode

 LH mode

 LL mode
Irradiator

 A compact linear accelerator A compact linear accelerator Precision radiation medicine company linac
Mean dose rate

 Gy/s

 468

 0.4

 0.1
Instantaneous dose rate

 Gy/s

 4.78×105

 1.02×105

 111
Total delivery time

 s

 0.02

 24

 100
Number of pulses

5

 24

 28600
Entrance Dose (1)

 Gy

 9.428 ± 0.131

 9.655 ±0.206

 9.534 ± 0.122
Exit dose (1)

 Gy

 10.24 ± 0.371

 10.71 ± 0.334

 10.26 ± 0.200
30-day survival fractions

4/7

 4/6

 0/6
White blood cell counts 3h post TBI (relative to control) (1)

1.176 ±0.224

 1.325 ±0.302

 0.852 ±0.153 (*, #)
White blood cell counts 48h post TBI (relative to control) (1)

0.362 ±0.098

 0.337 ±0.144

 0.073 ±0.020 (*, #)
Intestinal tissue ?-H2AX index 3h post TBI (1)

66.07 ±20.24

 76.07 ±14.36

 99.51 ±18.15 (*, #)
Intestinal tissue ?-H2AX index 48h post TBI (1)

8.71 ±2.20

 10.01 ±2.94

 13.31 ±2.03 (*)