title: Sub-micrometer 20MeV protons or 45MeV lithium spot irradiation enhances yields of dicentric chromosomes due to clustering of DNA double-strand breaks.
abstract: In conventional experiments on biological effects of radiation types of diverse quality, micrometer-scale double-strand break (DSB) clustering is inherently interlinked with clustering of energy deposition events on nanometer scale relevant for DSB induction. Due to this limitation, the role of the micrometer and nanometer scales in diverse biological endpoints cannot be fully separated. To address this issue, hybrid human-hamster AL cells have been irradiated with 45MeV (60keV/μm) lithium ions or 20MeV (2.6keV/μm) protons quasi-homogeneously distributed or focused to 0.5×1μm(2) spots on regular matrix patterns (point distances up to 10.6×10.6μm), with pre-defined particle numbers per spot to provide the same mean dose of 1.7Gy. The yields of dicentrics and their distribution among cells have been scored. In parallel, track-structure based simulations of DSB induction and chromosome aberration formation with PARTRAC have been performed. The results show that the sub-micrometer beam focusing does not enhance DSB yields, but significantly affects the DSB distribution within the nucleus and increases the chance to form DSB pairs in close proximity, which may lead to increased yields of chromosome aberrations. Indeed, the experiments show that focusing 20 lithium ions or 451 protons per spot on a 10.6μm grid induces two or three times more dicentrics, respectively, than a quasi-homogenous irradiation. The simulations reproduce the data in part, but in part suggest more complex behavior such as saturation or overkill not seen in the experiments. The direct experimental demonstration that sub-micrometer clustering of DSB plays a critical role in the induction of dicentrics improves the knowledge on the mechanisms by which these lethal lesions arise, and indicates how the assumptions of the biophysical model could be improved. It also provides a better understanding of the increased biological effectiveness of high-LET radiation.
authors.affiliation: Department of Radiation Oncology, Technische Universität München, Germany. Electronic address: Schmid@lrz.tu-muenchen.de.
authors.forename: T E
authors.initials: TE
authors.lastname: Schmid
authors.affiliation: Institute of Radiation Protection, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Friedland
authors.affiliation: Institute for Applied Physics and Metrology, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Greubel
authors.affiliation: Institute for Applied Physics and Metrology, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Girst
authors.affiliation: Institute for Applied Physics and Metrology, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Reindl
authors.affiliation: Department of Radiation Oncology, Technische Universität München, Germany; Institute for Applied Physics and Metrology, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Siebenwirth
authors.affiliation: Department of Radiation Oncology, Technische Universität München, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Ilicic
authors.affiliation: Department for Anatomy and Cell Biology, Ludwig-Maximilians Universität München, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schmid
authors.affiliation: Department of Radiation Oncology, Technische Universität München, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Multhoff
authors.affiliation: Institute of Radiation Protection, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Institute of Radiation Protection, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Kundrát
authors.affiliation: Institute for Applied Physics and Metrology, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Dollinger
mesh_terms: D000818:Animals; D016466:CHO Cells; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000528:radiation effects; D033481:Chromosomes, Mammalian / Q000528:radiation effects*; D003412:Cricetulus; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D006801:Humans; D008094:Lithium; D008957:Models, Genetic; D008962:Models, Theoretical; D011522:Protons; D012062:Relative Biological Effectiveness
chemical_list: D011522:Protons; D008094:Lithium
keywords: DSB distribution; Dicentric assay; Ion irradiation; Mathematical modeling; Microbeam