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Edited by Rodney Rothstein, Columbia University Medical Center, New York, NY, and approved August 24, 2015 (received for review May 12, 2015)
Significance
Charged particles are applied in cancer radiotherapy because they are more efficient than X-rays or γ-rays in tumor cell killing. This efficiency results from the high dose deposition along the path of the particles. However, charged particles damage tissue inhomogeneously, such that many cells not directly hit by the particles receive a low dose and can survive with mutations. Because mutations can lead to secondary malignancies, this effect limits the applicability of charged particles in cancer radiotherapy. We provide the first direct measurement of the 3D DNA lesion distribution induced by energetic charged particles in a mouse model tissue. Our detailed analysis of the dose distribution will serve to benchmark biophysical models currently used for irradiation planning in cancer radiotherapy.
Abstract
Charged particles are increasingly used in cancer radiotherapy and contribute significantly to the natural radiation risk. The difference in the biological effects of high-energy charged particles compared with X-rays or γ-rays is determined largely by the spatial distribution of their energy deposition events. Part of the energy is deposited in a densely ionizing manner in the inner part of the track, with the remainder spread out more sparsely over the outer track region. Our knowledge about the dose distribution is derived solely from modeling approaches and physical measurements in inorganic material. Here we exploited the exceptional sensitivity of γH2AX foci technology and quantified the spatial distribution of DNA lesions induced by charged particles in a mouse model tissue. We observed that charged particles damage tissue nonhomogenously, with single cells receiving high doses and many other cells exposed to isolated damage resulting from high-energy secondary electrons. Using calibration experiments, we transformed the 3D lesion distribution into a dose distribution and compared it with predictions from modeling approaches. We obtained a radial dose distribution with sub-micrometer resolution that decreased with increasing distance to the particle path following a 1/r2 dependency. The analysis further revealed the existence of a background dose at larger distances from the particle path arising from overlapping dose deposition events from independent particles. Our study provides, to our knowledge, the first quantification of the spatial dose distribution of charged particles in biologically relevant material, and will serve as a benchmark for biophysical models that predict the biological effects of these particles.
Footnotes
- ↵1To whom correspondence may be addressed. Email: t.friedrich{at}gsi.de or lobrich{at}bio.tu-darmstadt.de.
Author contributions: M.L. designed research; J.M., F.T., and A.F. performed research; J.M., F.T., A.F., S.C., M.D., M.S., T.F., and M.L. analyzed data; and J.M., T.F., and M.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1508702112/-/DCSupplemental.
Freely available online through the PNAS open access option.
DNA lesion distribution after particle irradiation
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