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Linking Single-Site DNA Damage Response to Individual Charged Particle Type in C-Ion Radiotherapy Beams

C McFadden1*, S Rahmanian2, D Flint1, S Bright1, D O'Brien1, A Aroumougame3, A Abdollahi2,4,5, S Greilich2, G Sawakuchi1
(1) MD Anderson Cancer Center, Houston, TX,(2) German Cancer Research Center (DKFZ), Heidelberg, Germany, (3) UT Southwestern, Dallas, TX,(4) National Center for Tumor Diseases (NCT), Heidelberg, Germany, (5) Ion-Beam Therapy Center (HIT), Heidelberg, Germany


(Tuesday, 7/31/2018) 1:45 PM - 3:45 PM

Room: Karl Dean Ballroom A1

Purpose: To devise a technique capable of simultaneously monitoring DNA repair dynamics and co-localizing damaged sites with individual charged particle tracks (CPTs) to understand how multi-LET fields influence DNA damage response.

Methods: We used HT1080 cells that express eYFP-53BP1 - a fluorescent marker for double strand break (DSB) repair. Cells were grown on coverslips made from fluorescent nuclear track detector (FNTD) to allow simultaneous visualization of individual CPTs and live cells. We assembled a portable fluorescence confocal laser-scanning microscope in a clinical C-ion beamline to visualize live cells and CPTs before, during and after irradiation. Cells were exposed to 0.5-Gy using a 4-8 cm SOBP at 0.7 and 7.2-cm water-equivalent depths and 53BP1 foci were recorded for 1-hour followed by FNTD readout to record CPTs. Foci brightness was used as the endpoint for DSB repair. CPT trajectories were directly linked to individual foci. Fluorescence intensities of CPTs were used to separate foci induced by primary C-ions from fragments.

Results: At 7.2-cm depth where the field is composed of Z=1-6 particles, DSB foci induced by primary C-ions were 1.33 times brighter at t=30 min than fragments. Fragment-induced DSB foci were 1.28 times brighter then x-ray induced foci at 30 min, as expected because the low-LET fragments are mainly high-energy protons. Our technique allows foci to be grouped in LET ranges for multi-LET fields. If foci intensity were simply averaged for all foci at the 7.2-cm depth, the average response would have been similar to that for the 0.7-cm depth. This would contradict cell survival data showing the 7.2-cm depth to have much higher RBE (2.83±0.08) than the 0.7-cm depth (1.85±0.05).

Conclusion: A few high-LET DSB lesions drive cell fate. This has important implications in the definition of average LET and also for combined biological consequences of multi-LET fields including C-ion therapy.


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