DNA damage in blood lymphocytes in patients after 177Lu peptide receptor radionuclide therapy

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Abstract

Purpose

The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-labelled DOTATATE/DOTATOC.

Methods

The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time–activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with ¹³¹I and ¹⁷⁷Lu.

Results

The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair.

Conclusion

Measurements of RIF and the absorbed dose to the blood after systemic administration of ¹⁷⁷Lu may be used to obtain data on the individual dose–response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair.

Electronic supplementary material

The online version of this article (doi:10.1007/s00259-015-3083-9) contains supplementary material, which is available to authorized users.

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Most cited references 42

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Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.

K. Rothkamm, M Löbrich (2003)

DNA double-strand breaks (DSBs) are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease. However, no information on the induction and processing of DSBs after physiologically relevant radiation doses is available. Many of the methods used to measure DSB repair inadvertently introduce this form of damage as part of the methodology, and hence are limited in their sensitivity. Here we present evidence that foci of gamma-H2AX (a phosphorylated histone), detected by immunofluorescence, are quantitatively the same as DSBs and are capable of quantifying the repair of individual DSBs. This finding allows the investigation of DSB repair after radiation doses as low as 1 mGy, an improvement by several orders of magnitude over current methods. Surprisingly, DSBs induced in cultures of nondividing primary human fibroblasts by very low radiation doses (approximately 1 mGy) remain unrepaired for many days, in strong contrast to efficient DSB repair that is observed at higher doses. However, the level of DSBs in irradiated cultures decreases to that of unirradiated cell cultures if the cells are allowed to proliferate after irradiation, and we present evidence that this effect may be caused by an elimination of the cells carrying unrepaired DSBs. The results presented are in contrast to current models of risk assessment that assume that cellular responses are equally efficient at low and high doses, and provide the opportunity to employ gamma-H2AX foci formation as a direct biomarker for human exposure to low quantities of ionizing radiation.

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P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand Breaks

Linda Schultz, Nabil Chehab, Asra Malikzay … (2000)

p53 binding protein 1 (53BP1), a protein proposed to function as a transcriptional coactivator of the p53 tumor suppressor, has BRCT domains with high homology to the Saccharomyces cerevisiae Rad9p DNA damage checkpoint protein. To examine whether 53BP1 has a role in the cellular response to DNA damage, we probed its intracellular localization by immunofluorescence. In untreated primary cells and U2OS osteosarcoma cells, 53BP1 exhibited diffuse nuclear staining; whereas, within 5–15 min after exposure to ionizing radiation (IR), 53BP1 localized at discreet nuclear foci. We propose that these foci represent sites of processing of DNA double-strand breaks (DSBs), because they were induced by IR and chemicals that cause DSBs, but not by ultraviolet light; their peak number approximated the number of DSBs induced by IR and decreased over time with kinetics that parallel the rate of DNA repair; and they colocalized with IR-induced Mre11/NBS and γ-H2AX foci, which have been previously shown to localize at sites of DSBs. Formation of 53BP1 foci after irradiation was not dependent on ataxia-telangiectasia mutated (ATM), Nijmegen breakage syndrome (NBS1), or wild-type p53. Thus, the fast kinetics of 53BP1 focus formation after irradiation and the lack of dependency on ATM and NBS1 suggest that 53BP1 functions early in the cellular response to DNA DSBs.

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Is Open Access

Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research.

Alesia Ivashkevich, Christophe E. Redon, Asako Nakamura … (2012)

Formation of γ-H2AX in response to DNA double stranded breaks (DSBs) provides the basis for a sensitive assay of DNA damage in human biopsies. The review focuses on the application of γ-H2AX-based methods to translational studies to monitor the clinical response to DNA targeted therapies such as some forms of chemotherapy, external beam radiotherapy, radionuclide therapy or combinations thereof. The escalating attention on radiation biodosimetry has also highlighted the potential of the assay including renewed efforts to assess the radiosensitivity of prospective radiotherapy patients. Finally the γ-H2AX response has been suggested as a basis for an in vivo imaging modality. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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Author and article information

Contributors

Uta Eberlein: +49-931-20135415 , eberlein_u@klinik.uni-wuerzburg.de

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur. J. Nucl. Med. Mol. Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 6 June 2015

Publication date PMC-release: 6 June 2015

Publication date (Print): 2015

Volume: 42

Issue: 11

Pages: 1739-1749

Affiliations

[ ]Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany

[ ]Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, 80937 Munich, Germany

Article

Publisher ID: 3083

DOI: 10.1007/s00259-015-3083-9

PMC ID: 4554740

PubMed ID: 26048612

SO-VID: efdcb600-bd7a-4838-9024-ebc1ab28f340

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 20 March 2015

Date accepted : 5 May 2015

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ScienceOpen disciplines: Radiology & Imaging

Keywords: γ-h2ax,53bp1,biological dosimetry,peptide receptor radionuclide therapy,absorbed dose to blood,dsb focus assay,dna damage,177lu,ionizing radiation

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ScienceOpen disciplines: Radiology & Imaging

Keywords: γ-h2ax, 53bp1, biological dosimetry, peptide receptor radionuclide therapy, absorbed dose to blood, dsb focus assay, dna damage, 177lu, ionizing radiation

DNA damage in blood lymphocytes in patients after ¹⁷⁷Lu peptide receptor radionuclide therapy

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Most cited references 42

Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.

P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand Breaks

Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research.

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