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Ultra-high dose-rate proton DNA damage changed with scavenger concentration and dose

Ultra-high dose-rate protons produced fewer DNA breaks at low scavenger concentration, but the effect diminished or reversed under other experimental conditions.

RadOncToday · ·1 min read

KEY POINTS

  • The experiment used cell-free pUC-19 plasmid DNA in either 2 or 10 mM HEPES and compared ultra-high dose-rate with conventional proton irradiation at 1 and 3 kGy, both in low-linear-energy-transfer plateau and higher-linear-energy-transfer Bragg-peak regions. Approximately 1,000 DNA fragments per condition were measured by atomic force microscopy.
  • Ultra-high dose-rate irradiation used a 142.4 MeV synchrotron pencil-beam scanning beam, delivering approximately 1.2 kGy per spill. Conventional irradiation used a separate 110 MeV proton system at 2 Gy/min. Dose-averaged linear energy transfer was approximately 1.0–1.1 keV/μm at the plateau and 8.5 keV/μm near the Bragg peak.
  • At 2 mM HEPES and 1 kGy, ultra-high dose-rate irradiation produced fewer double-strand breaks per plasmid than conventional irradiation at both the plateau (0.74 vs 0.92; p<0.05) and Bragg peak (0.80 vs 0.98; p<0.05).
  • At 3 kGy and 2 mM HEPES, the same direction persisted at the plateau (1.74 vs 2.11 breaks per plasmid; p<0.05), while the Bragg-peak difference was smaller and non-significant (2.05 vs 2.15).
  • Increasing scavenger concentration to 10 mM largely removed the difference at 1 kGy: double-strand-break yields were 0.68 vs 0.70 at the plateau and 0.76 vs 0.83 at the Bragg peak, neither statistically significant.
  • At 3 kGy and 10 mM HEPES, the pattern reversed at the Bragg peak: ultra-high dose-rate irradiation produced 2.01 versus 1.45 double-strand breaks per plasmid (p<0.001). DNA fragmentation was likewise higher at 74.9% versus 57.9% (p<0.001). At the plateau, break rates were similar (1.59 vs 1.54).
  • The model deliberately isolates physicochemical DNA damage from cellular repair, oxygen dynamics, metabolism and immune effects. The use of different proton machines and extremely high kilogray doses further means these results cannot be translated directly into normal-tissue sparing in patients.

CLINICAL TAKEAWAY

The data argue against treating the FLASH effect as a simple consequence of dose rate alone: radical chemistry, total dose and linear energy transfer substantially altered the direction and magnitude of DNA damage. This is mechanistic evidence, not evidence that a particular proton FLASH regimen will spare normal tissue clinically.

SOURCE

International Journal of Radiation Oncology, Biology, Physics