Biological Effects of Monoenergetic Carbon Ions and Their Associated Secondary Particles.

Dylan J Buglewicz,Hisashi Kitamura,Takamitsu A Kato,Kade D Walsh,Akira Fujimori,Hirokazu Hirakawa

doi:10.3389/fonc.2022.788293

Abstract

DNA double-strand breaks (DSBs) are the main factor behind carbon-ion radiation therapy (CIRT)-induced cell death. Nuclear interactions along the beam path between the primary carbon ions and targets result in nuclear fragmentation of carbon ions and recoiled particles. These secondary particles travel further distances past the Bragg peak to the tail region, leading to unwanted biological effects that may result in cytotoxicity in critical organs and secondary induced tumors following CIRT. Here, we confirmed that the density of the DSB distributions increases as the cell survival decreases at the Bragg peak and demonstrated that by visualizing DSBs, the various LET fragmentation ions and recoiled particles produced differences in their biological effects in the post-Bragg peak tail regions. This suggests that the density of the DSBs within the high-LET track structures, rather than only their presence, is important for inducing cell death. These results are essential for CIRT treatment planning to limit the amount of healthy cell damage and reducing both the late effect and the secondary tumor-associated risk.

Highlights

The most consequential of the ionizing radiation-induced DNA damage lesions are DNA doublestrand breaks (DSBs)
We observed a sharp decrease in survival fractions the closer the depth was to the Bragg peak, with the lowest survival fraction being observed at 140 mm in depth, regardless of initial treatment dosage, and a slight difference of 2 mm with physical dose distribution (Figures 1B, C)
One possibility is due to the heterogeneity of beam quality, e.g., the monoenergetic beam is not perfectly monoenergetic meaning that some fraction of carbon ions may be of higher energy allowing for them to travel further [12]. Another possible reason explaining this observation may be due to the secondary particles from nuclear fragmentation of the initial carbon ions and recoiled particles, as these fragmentation ions and recoiled particles are known to be capable of traveling longer distances past the Bragg peak [28]

Summary

Introduction

The most consequential of the ionizing radiation-induced DNA damage lesions are DNA doublestrand breaks (DSBs). High linear energy transfer (LET) radiation includes alpha particles, carbon, and iron ions which deposit their energy within densely ionizing tracks that are created by the particle’s traversal through the cell This allows for the formation of multiple close-proximity DNA damages including DSBs, single-strand breaks (SSBs), and base damages following high LET irradiation. Such complex DNA damage has been demonstrated in prior studies using clusters of g-H2AX foci as a surrogate marker for DSBs by horizontal irradiation and high-resolution microscopy [4–6]. These clustered DSBs are DNA damage Carbon Bragg Peak known to be very difficult for the cell to repair and may be a strong contributor to genomic instability [7, 8]

Methods

Results

Conclusion