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Double Strand Break (DSB) Complexity and Proximity Effects Within the Repair-Misrepair Fixation (RMF) Model for Improved Predictions of Cell Survival From Heavy Ions

M Butkus1*, R Stewart2 , Z Chen1 , D Carlson1 , (1) Yale university School of Medicine, New Haven, CT, (2) University of Washington, Seattle, WA


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

Room: Karl Dean Ballroom A1

Purpose: For ions of Z>2, the repair-misrepair-fixation (RMF) model does not fully capture the trend of decreasing relative biological effectiveness (RBE) as a particle’s linear energy transfer (LET) increases beyond about 150-200 keV/μm. In this work, the effects of local DNA double strand break (DSB) complexity and proximity effects are examined within the RMF model. DSB complexity tends to slow the kinetics of the DNA repair process whereas we hypothesize that two or more DSBs, separated by a few tens or hundreds of base pair (bp), may be effectively processed by DNA repair mechanisms as a single DSB.

Methods: The Monte Carlo Damage Simulation (MCDC3.10A) was used to predict absolute DSB Gy�¹ Gbp�¹ for ions with (Zeff/β)² up to 10,000. The effective volume over which two or more DSB are treated as a single DSB was estimated by minimizing the mean log-squared error between RMF model estimates and measured cell survival data for V79, HSG, and T1 cells irradiated by helium-3, carbon-12 and neon-20 ions under aerobic and hypoxic conditions.

Results: The diameter of the volume underlying the proximity effect was estimated as 2-10 nm. For aerobic V79 cells, inclusion of a proximity factor results in an effective maximum of 14.66 DSB Gy�¹Gbp�¹ at (Zeff/β)²=859.1 and a subsequent decrease to 4.94 DSB Gy�¹ Gbp�¹ at (Zeff/β)²=10,000. These are reductions from absolute yields of 19.2 and 27.7 DSB Gy�¹ Gbp�¹, respectively. The reduction in the effective DSB yield with increasing LET suffices to explain the downward trend in particle RBE for high LET particles, which in turn increases the accuracy of cellular survival predictions from the RMF.

Conclusion: A refined RMF model that corrects for local DSB complexity and proximity effects on a nanometer scale captures the downward trends in RBE for cell survival with increasing LET for Z>2 ions.


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