The Fate of a Normal Human Cell Traversed by a Single Charged Particle

Fournier, Claudia; Zahnreich, Sebastian; Kraft, Daniela; Friedrich, Thomas; Voss, Kay‐Obbe; Durante, Marco; Ritter, S.

doi:10.1038/srep00643

Cited by 23 publications

(16 citation statements)

References 35 publications

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“…In addition, a connection between elevated levels of ROS, an impeded oxidative defense and the accumulation of chromosomal damage has been reported in X-irradiated human tumor cells [ 10 ]. In foreskin fibroblasts (AG1522), however, an increased long-term chromosomal instability was not observed in our previous studies [ 18 , 19 ]. Therefore, we addressed the question of whether increased ROS levels occur in AG1522 fibroblasts that do not show chromosomal instability.…”

Section: Introductionmentioning

confidence: 60%

Increased effectiveness of carbon ions in the production of reactive oxygen species in normal human fibroblasts

Dettmering

Zahnreich

Colindres-Rojas

et al. 2014

Journal of Radiation Research

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The production of reactive oxygen species (ROS), especially superoxide anions (O2·–), is enhanced in many normal and tumor cell types in response to ionizing radiation. The influence of ionizing radiation on the regulation of ROS production is considered as an important factor in the long-term effects of irradiation (such as genomic instability) that might contribute to the development of secondary cancers. In view of the increasing application of carbon ions in radiation therapy, we aimed to study the potential impact of ionizing density on the intracellular production of ROS, comparing photons (X-rays) with carbon ions. For this purpose, we used normal human cells as a model for irradiated tissue surrounding a tumor. By quantifying the oxidization of Dihydroethidium (DHE), a fluorescent probe sensitive to superoxide anions, we assessed the intracellular ROS status after radiation exposure in normal human fibroblasts, which do not show radiation-induced chromosomal instability. After 3–5 days post exposure to X-rays and carbon ions, the level of ROS increased to a maximum that was dose dependent. The maximum ROS level reached after irradiation was specific for the fibroblast type. However, carbon ions induced this maximum level at a lower dose compared with X-rays. Within ∼1 week, ROS decreased to control levels. The time-course of decreasing ROS coincides with an increase in cell number and decreasing p21 protein levels, indicating a release from radiation-induced growth arrest. Interestingly, radiation did not act as a trigger for chronically enhanced levels of ROS months after radiation exposure.

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Section: Introductionmentioning

confidence: 60%

Increased effectiveness of carbon ions in the production of reactive oxygen species in normal human fibroblasts

Dettmering

Zahnreich

Colindres-Rojas

et al. 2014

Journal of Radiation Research

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“…As highlighted in Table and the corresponding discussion, RBE effects are believed to arise as a result of DSB interactions in molecular and cellular targets and the ionization density along the trajectory of an ion (i.e., the track structure) and among cells. Focused particle microbeams are a potentially effective way to probe the interaction of the DSB formed along different particle tracks. For example, Girst et al .…”

Section: Model Testing and Clinical Validation Of Rbe Modelsmentioning

confidence: 99%

“…As highlighted in Table IV and the corresponding discussion, RBE effects are believed to arise as a result of DSB interactions in molecular and cellular targets and the ionization density along the trajectory of an ion (i.e., the track structure) and among cells. Focused particle microbeams [152][153][154][155][156][157][158][159] are a potentially effective way to probe the interaction of the DSB formed along different particle tracks. For example, Girst et al 160 used live-cell observations and distance tracking of the GFP-tagged DNA damage response protein MDC1 to study the random-walk behavior of DSB formed in chromatin domains by 20 MeV proton and 43 MeV carbon ions.…”

Section: Model Testing and Clinical Validation Of Rbe Modelsmentioning

confidence: 99%

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

et al. 2018

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Background and Significance The application of heavy ion beams in cancer therapy must account for the increasing relative biological effectiveness (RBE) with increasing penetration depth when determining dose prescriptions and organ at risk (OAR) constraints in treatment planning. Because RBE depends in a complex manner on factors such as the ion type, energy, cell and tissue radiosensitivity, physical dose, biological endpoint, and position within and outside treatment fields, biophysical models reflecting these dependencies are required for the personalization and optimization of treatment plans. Aim To review and compare three mechanism‐inspired models which predict the complexities of particle RBE for various ion types, energies, linear energy transfer (LET) values and tissue radiation sensitivities. Methods The review of models and mechanisms focuses on the Local Effect Model (LEM), the Microdosimetric‐Kinetic (MK) model, and the Repair‐Misrepair‐Fixation (RMF) model in combination with the Monte Carlo Damage Simulation (MCDS). These models relate the induction of potentially lethal double strand breaks (DSBs) to the subsequent interactions and biological processing of DSB into more lethal forms of damage. A key element to explain the increased biological effectiveness of high LET ions compared to MV x rays is the characterization of the number and local complexity (clustering) of the initial DSB produced within a cell. For high LET ions, the spatial density of DSB induction along an ion's trajectory is much greater than along the path of a low LET electron, such as the secondary electrons produced by the megavoltage (MV) x rays used in conventional radiation therapy. The main aspects of the three models are introduced and the conceptual similarities and differences are critiqued and highlighted. Model predictions are compared in terms of the RBE for DSB induction and for reproductive cell survival. Results and Conclusions Comparisons of the RBE for DSB induction and for cell survival are presented for proton (1H), helium (4He), and carbon (12C) ions for the therapeutically most relevant range of ion beam energies. The reviewed models embody mechanisms of action acting over the spatial scales underlying the biological processing of potentially lethal DSB into more lethal forms of damage. Differences among the number and types of input parameters, relevant biological targets, and the computational approaches among the LEM, MK and RMF models are summarized and critiqued. Potential experiments to test some of the seemingly contradictory aspects of the models are discussed.

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“…The occurrence of IR-induced instability was shown to be further delayed in late passages after irradiation with higher LET IR [91,92]; therefore, it can be concluded that high-LET IR has a higher capacity to induce delayed genomic instability compared to low-LET IR [102]. Furthermore, long-term instability can even be induced by a single alpha-particle [103] or carbon ion [104] from a focused microbeam, as well as following cytoplasmic irradiation with alpha particles [105,106]. Eventually, these IR-induced or pre-existing recessive mutations may be unmasked and amplified, and upon loss of tumor suppressor function, those cells that harbor genetic alterations that give them a proliferative advantage invade the cell population.…”

Section: Telomere Maintenance and The Effects Of Ionizing Radiationmentioning

confidence: 99%

Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis

Shim

Ricoul

Hempel

et al. 2014

Mutation Research/Reviews in Mutation Research

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It is well established that ionizing radiation induces chromosomal damage, both following direct radiation exposure and via non-targeted (bystander) effects, activating DNA damage repair pathways, of which the proteins are closely linked to telomeric proteins and telomere maintenance. Long-term propagation of this radiation-induced chromosomal damage during cell proliferation results in chromosomal instability. Many studies have shown the link between radiation exposure and radiation-induced changes in oxidative stress and DNA damage repair in both targeted and non-targeted cells. However, the effect of these factors on telomeres, long established as guardians of the genome, still remains to be clarified. In this review, we will focus on what is known about how telomeres are affected by exposure to low- and high-LET ionizing radiation and during proliferation, and will discuss how telomeres may be a key player in the process of radiation-induced carcinogenesis.

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The Fate of a Normal Human Cell Traversed by a Single Charged Particle

Cited by 23 publications

References 35 publications

Increased effectiveness of carbon ions in the production of reactive oxygen species in normal human fibroblasts

Increased effectiveness of carbon ions in the production of reactive oxygen species in normal human fibroblasts

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis

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