Inter-individual and inter-cell type variation in residual DNA damage after in vivo irradiation of human skin

Chua, Melvin L.K.; Somaiah, Navita; Bourne, S.; Daley, Frances; A’Hern, Roger; Nuta, Otilia; Davies, SE; Herskind, Carsten; Pearson, Alex; Warrington, Jim; Helyer, Sarah; Owen, Roger; Yarnold, John; Rothkamm, Kai

doi:10.1016/j.radonc.2011.04.009

Cited by 22 publications

(23 citation statements)

References 26 publications

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“…Together, these factors may explain the five-fold discrepancy between foci yields in fibroblast cultures and skin sections obtained in this study. Nonetheless, this study confirms previous work indicating that chromogenic immunohistochemical staining can be used to quantify ionising radiation-induced foci in tissue sections [23], [24].…”

Section: Discussionsupporting

confidence: 90%

In situ Biological Dose Mapping Estimates the Radiation Burden Delivered to ‘Spared’ Tissue between Synchrotron X-Ray Microbeam Radiotherapy Tracks

et al. 2012

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Microbeam radiation therapy (MRT) using high doses of synchrotron X-rays can destroy tumours in animal models whilst causing little damage to normal tissues. Determining the spatial distribution of radiation doses delivered during MRT at a microscopic scale is a major challenge. Film and semiconductor dosimetry as well as Monte Carlo methods struggle to provide accurate estimates of dose profiles and peak-to-valley dose ratios at the position of the targeted and traversed tissues whose biological responses determine treatment outcome. The purpose of this study was to utilise γ-H2AX immunostaining as a biodosimetric tool that enables in situ biological dose mapping within an irradiated tissue to provide direct biological evidence for the scale of the radiation burden to ‘spared’ tissue regions between MRT tracks. Γ-H2AX analysis allowed microbeams to be traced and DNA damage foci to be quantified in valleys between beams following MRT treatment of fibroblast cultures and murine skin where foci yields per unit dose were approximately five-fold lower than in fibroblast cultures. Foci levels in cells located in valleys were compared with calibration curves using known broadbeam synchrotron X-ray doses to generate spatial dose profiles and calculate peak-to-valley dose ratios of 30–40 for cell cultures and approximately 60 for murine skin, consistent with the range obtained with conventional dosimetry methods. This biological dose mapping approach could find several applications both in optimising MRT or other radiotherapeutic treatments and in estimating localised doses following accidental radiation exposure using skin punch biopsies.

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Section: Discussionsupporting

confidence: 90%

In situ Biological Dose Mapping Estimates the Radiation Burden Delivered to ‘Spared’ Tissue between Synchrotron X-Ray Microbeam Radiotherapy Tracks

et al. 2012

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“…All the donors included in this study had spontaneous foci levels of <0.2 per cell; accordingly at 24 hours post exposure a level of 0.2 foci per cell would give a dose estimate of ∼100 mGy. It should be noted that background levels of spontaneous foci observed here and in published in/ex vivo studies using peripheral blood lymphocytes [8], [11], [12] or other primary human quiescent cells [26] are lower than those reported for established cell lines, especially those derived from tumours (e.g. [27]).…”

Section: Discussioncontrasting

confidence: 69%

Gamma-H2AX-Based Dose Estimation for Whole and Partial Body Radiation Exposure

Horn

Barnard²,

Rothkamm³

2011

PLoS ONE

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147

118

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Most human exposures to ionising radiation are partial body exposures. However, to date only limited tools are available for rapid and accurate estimation of the dose distribution and the extent of the body spared from the exposure. These parameters are of great importance for emergency triage and clinical management of exposed individuals. Here, measurements of γ-H2AX immunofluorescence by microscopy and flow cytometry were compared as rapid biodosimetric tools for whole and partial body exposures. Ex vivo uniformly X-irradiated blood lymphocytes from one donor were used to generate a universal biexponential calibration function for γ-H2AX foci/intensity yields per unit dose for time points up to 96 hours post exposure. Foci – but not intensity – levels remained significantly above background for 96 hours for doses of 0.5 Gy or more. Foci-based dose estimates for ex vivo X-irradiated blood samples from 13 volunteers were in excellent agreement with the actual dose delivered to the targeted samples. Flow cytometric dose estimates for X-irradiated blood samples from 8 volunteers were in excellent agreement with the actual dose delivered at 1 hour post exposure but less so at 24 hours post exposure. In partial body exposures, simulated by mixing ex vivo irradiated and unirradiated lymphocytes, foci/intensity distributions were significantly over-dispersed compared to uniformly irradiated lymphocytes. For both methods and in all cases the estimated fraction of irradiated lymphocytes and dose to that fraction, calculated using the zero contaminated Poisson test and γ-H2AX calibration function, were in good agreement with the actual mixing ratios and doses delivered to the samples. In conclusion, γ-H2AX analysis of irradiated lymphocytes enables rapid and accurate assessment of whole body doses while dispersion analysis of foci or intensity distributions helps determine partial body doses and the irradiated fraction size in cases of partial body exposures.

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“…Detection of X-ray induced DNA double strand breaks (DSBs) by gamma-H2AX foci/intensity quantification has proved useful for biological dosimetry [3] and for investigating intra-cell and inter-individual responses to low linear energy transfer (LET) radiation [4]. For high LET exposures, such as those induced by heavy ions or alpha particles, slower repair of DSBs has been observed, likely due to the greater complexity and subsequent greater difficulty in resolving the break [5].…”

Section: Introductionmentioning

confidence: 99%

Alpha particles induce pan-nuclear phosphorylation of H2AX in primary human lymphocytes mediated through ATM

Horn

Brady

Prise

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The use of high linear energy transfer radiations in the form of carbon ions in heavy ion beam lines or alpha particles in new radionuclide treatments has increased substantially over the past decade and will continue to do so due to the favourable dose distributions they can offer versus conventional therapies. Previously it has been shown that exposure to heavy ions induces pan-nuclear phosphorylation of several DNA repair proteins such as H2AX and ATM in vitro. Here we describe similar effects of alpha particles on ex vivo irradiated primary human peripheral blood lymphocytes. Following alpha particle irradiation pan-nuclear phosphorylation of H2AX and ATM, but not DNA-PK and 53BP1, was observed throughout the nucleus. Inhibition of ATM, but not DNA-PK, resulted in the loss of pan-nuclear phosphorylation of H2AX in alpha particle irradiated lymphocytes. Pan-nuclear gamma-H2AX signal was rapidly lost over 24h at a much greater rate than foci loss. Surprisingly, pan-nuclear gamma-H2AX intensity was not dependent on the number of alpha particle induced double strand breaks, rather the number of alpha particles which had traversed the cell nucleus. This distinct fluence dependent damage signature of particle radiation is important in both the fields of radioprotection and clinical oncology in determining radionuclide biological dosimetry and may be indicative of patient response to new radionuclide cancer therapies.

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Inter-individual and inter-cell type variation in residual DNA damage after in vivo irradiation of human skin

Cited by 22 publications

References 26 publications

In situ Biological Dose Mapping Estimates the Radiation Burden Delivered to ‘Spared’ Tissue between Synchrotron X-Ray Microbeam Radiotherapy Tracks

In situ Biological Dose Mapping Estimates the Radiation Burden Delivered to ‘Spared’ Tissue between Synchrotron X-Ray Microbeam Radiotherapy Tracks

Gamma-H2AX-Based Dose Estimation for Whole and Partial Body Radiation Exposure

Alpha particles induce pan-nuclear phosphorylation of H2AX in primary human lymphocytes mediated through ATM

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