Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

Open Access 01-10-2015 | Original Article

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

Authors: Uta Eberlein, Carina Nowak, Christina Bluemel, Andreas Konrad Buck, Rudolf Alexander Werner, Harry Scherthan, Michael Lassmann

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 11/2015

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.

Available only for authorised users

Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;40:800–16.PubMedCentralCrossRefPubMed

Baum RP, Kulkarni HR. Peptide receptor radionuclide therapy of neuroendocrine tumors expressing somatostatin receptors. In: Baum RP, editor. Therapeutic Nuclear Medicine. Berlin: Springer; 2014. p. 583–603.CrossRef

Van Essen M, Krenning EP, De Jong M, Valkema R, Kwekkeboom DJ. Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. Acta Oncol. 2007;46:723–34.CrossRefPubMed

Van Essen M, Krenning EP, Kooij PP, Bakker WH, Feelders RA, de Herder WW, et al. Effects of therapy with [¹⁷⁷Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med. 2006;47:1599–606.

Bartolomei M, Bodei L, De Cicco C, Grana CM, Cremonesi M, Botteri E, et al. Peptide receptor radionuclide therapy with (90)Y-DOTATOC in recurrent meningioma. Eur J Nucl Med Mol Imaging. 2009;36:1407–16.CrossRefPubMed

Sabet A, Ahmadzadehfar H, Herrlinger U, Wilinek W, Biersack H-J, Ezziddin S. Successful radiopeptide targeting of metastatic anaplastic meningioma: case report. Radiat Oncol. 2011;6:94.PubMedCentralCrossRefPubMed

Kreissl MC, Hänscheid H, Löhr M, Verburg FA, Schiller M, Lassmann M, et al. Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma. Radiat Oncol. 2012;7:99.PubMedCentralCrossRefPubMed

Budiawan H, Salavati A, Kulkarni HR, Baum RP. Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using ⁹⁰Yttrium and ¹⁷⁷Lutetium labeled somatostatin analogs: toxicity, response and survival analysis. Am J Nucl Med Mol Imaging. 2013;4:39–52.

Lapa C, Werner RA, Schmid J-S, Papp L, Zsótér N, Biko J, et al. Prognostic value of positron emission tomography-assessed tumor heterogeneity in patients with thyroid cancer undergoing treatment with radiopeptide therapy. Nucl Med Biol. 2014. doi:10.1016/j.nucmedbio.2014.12.006.PubMed

10.

Versari A, Sollini M, Frasoldati A, Fraternali A, Filice A, Froio A, et al. Differentiated thyroid cancer: a new perspective with radiolabeled somatostatin analogues for imaging and treatment of patients. Thyroid. 2014;24:715–26.CrossRefPubMed

11.

Walrand S, Barone R, Pauwels S, Jamar F. Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts. Eur J Nucl Med Mol Imaging. 2011;38:1270–80.CrossRefPubMed

12.

Lassmann M, Eberlein U. Radiation dosimetry aspects of ¹⁷⁷Lu. Curr Radiopharm. 2015;8.

13.

Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–35.

14.

Glatting G, Bardiès M, Lassmann M. Treatment planning in molecular radiotherapy. Z Für Med Phys. 2013;23:262–9.CrossRef

15.

Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68.CrossRefPubMed

16.

Takahashi A, Ohnishi T. Does gammaH2AX foci formation depend on the presence of DNA double strand breaks? Cancer Lett. 2005;229:171–9.CrossRefPubMed

17.

Kuo LJ, Yang L-X. Gamma-H2AX – a novel biomarker for DNA double-strand breaks. In Vivo. 2008;22:305–9.PubMed

18.

Rothkamm K, Löbrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci U S A. 2003;100:5057–62.PubMedCentralCrossRefPubMed

19.

Ivashkevich A, Redon CE, Nakamura AJ, Martin RF, Martin OA. Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Lett. 2012;327:123–33.PubMedCentralCrossRefPubMed

20.

Schultz LB, Chehab NH, Malikzay A, Halazonetis TD. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol. 2000;151:1381–90.PubMedCentralCrossRefPubMed

21.

Anderson L, Henderson C, Adachi Y. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol Cell Biol. 2001;21:1719–29.PubMedCentralCrossRefPubMed

22.

Rappold I, Iwabuchi K, Date T, Chen J. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J Cell Biol. 2001;153:613–20.PubMedCentralCrossRefPubMed

23.

Huyen Y, Zgheib O, DiTullio Jr RA, Gorgoulis VG, Zacharatos P, Petty TJ, et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature. 2004;432:406–11.CrossRefPubMed

24.

Panier S, Boulton SJ. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol. 2014;15:7–18.CrossRefPubMed

25.

Ward IM, Minn K, Jorda KG, Chen J. Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX. J Biol Chem. 2003;278:19579–82.CrossRefPubMed

26.

Lamkowski A, Forcheron F, Agay D, Ahmed EA, Drouet M, Meineke V, et al. DNA damage focus analysis in blood samples of minipigs reveals acute partial body irradiation. PLoS ONE. 2014;9, e87458.PubMedCentralCrossRefPubMed

27.

Eberlein U, Peper M, Fernández M, Lassmann M, Scherthan H. Calibration of the γ-H2AX DNA double strand break focus assay for internal radiation exposure of blood lymphocytes. PLoS ONE. 2015;10, e0123174.PubMedCentralCrossRefPubMed

28.

Chowdhury D, Keogh M-C, Ishii H, Peterson CL, Buratowski S, Lieberman J. γ-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell. 2005;20:801–9.CrossRefPubMed

29.

Lassmann M, Hänscheid H, Gassen D, Biko J, Meineke V, Reiners C, et al. In vivo formation of gamma-H2AX and 53BP1 DNA repair foci in blood cells after radioiodine therapy of differentiated thyroid cancer. J Nucl Med. 2010;51:1318–25.CrossRefPubMed

30.

Doai M, Watanabe N, Takahashi T, Taniguchi M, Tonami H, Iwabuchi K, et al. Sensitive immunodetection of radiotoxicity after iodine-131 therapy for thyroid cancer using γ-H2AX foci of DNA damage in lymphocytes. Ann Nucl Med. 2013;27:233–8.CrossRefPubMed

31.

Denoyer D, Lobachevsky P, Jackson P, Thompson M, Martin OA, Hicks RJ. Analysis of ¹⁷⁷Lu-octreotate therapy-induced DNA damage in peripheral blood lymphocytes of patients with neuroendocrine tumors. J Nucl Med. 2015;56:505–11.

32.

Lassmann M, Hänscheid H, Chiesa C, Hindorf C, Flux G, Luster M. EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging. 2008;35:1405–12.CrossRefPubMed

33.

Beels L, Werbrouck J, Thierens H. Dose response and repair kinetics of gamma-H2AX foci induced by in vitro irradiation of whole blood and T-lymphocytes with X- and gamma-radiation. Int J Radiat Biol. 2010;86:760–8.CrossRefPubMed

34.

Löbrich M, Rief N, Kühne M, Heckmann M, Fleckenstein J, Rübe C, et al. In vivo formation and repair of DNA double-strand breaks after computed tomography examinations. Proc Natl Acad Sci U S A. 2005;102:8984–9.PubMedCentralCrossRefPubMed

35.

May M, Brand M, Wuest W, Anders K, Kuwert T, Prante O, et al. Induction and repair of DNA double-strand breaks in blood lymphocytes of patients undergoing ¹⁸F-FDG PET/CT examinations. Eur J Nucl Med Mol Imaging. 2012;39:1712–9.

36.

Sak A, Stuschke M. Use of γH2AX and other biomarkers of double-strand breaks during radiotherapy. Semin Radiat Oncol. 2010;20:223–31.CrossRefPubMed

37.

Dale RG, Fowler JF. Radiation repair mechanisms. In: Dale RG, Jones B, editors. Radiobiological modelling in radiation oncology. London: British Institute of Radiology; 2007.

38.

Fowler JF. Is repair of DNA strand break damage from ionizing radiation second-order rather than first-order? A simpler explanation of apparently multiexponential repair. Radiat Res. 1999;152:124–36.CrossRefPubMed

39.

Dale RG, Fowler JF, Jones B. A new incomplete-repair model based on a “reciprocal-time” pattern of sublethal damage repair. Acta Oncol Stockh Swed. 1999;38:919–29.CrossRef

40.

Horn S, Barnard S, Rothkamm K. Gamma-H2AX-based dose estimation for whole and partial body radiation exposure. PLoS ONE. 2011;6, e25113.PubMedCentralCrossRefPubMed

41.

Mariotti LG, Pirovano G, Savage KI, Ghita M, Ottolenghi A, Prise KM, et al. Use of the γ-H2AX assay to investigate DNA repair dynamics following multiple radiation exposures. PLoS ONE. 2013;8, e79541.PubMedCentralCrossRefPubMed

42.

Ivashkevich AN, Martin OA, Smith AJ, Redon CE, Bonner WM, Martin RF, et al. γH2AX foci as a measure of DNA damage: a computational approach to automatic analysis. Mutat Res. 2011;711:49–60.PubMedCentralCrossRefPubMed

43.

Rothkamm K, Balroop S, Shekhdar J, Fernie P, Goh V. Leukocyte DNA damage after multi-detector row CT: a quantitative biomarker of low-level radiation exposure. Radiology. 2007;242:244–51.CrossRefPubMed

44.

Golfier S, Jost G, Pietsch H, Lengsfeld P, Eckardt-Schupp F, Schmid E, et al. Dicentric chromosomes and gamma-H2AX foci formation in lymphocytes of human blood samples exposed to a CT scanner: a direct comparison of dose response relationships. Radiat Prot Dosim. 2009;134:55–61.CrossRef

45.

Beels L, Bacher K, De Wolf D, Werbrouck J, Thierens H. Gamma-H2AX foci as a biomarker for patient X-ray exposure in pediatric cardiac catheterization: are we underestimating radiation risks? Circulation. 2009;120:1903–9.CrossRefPubMed

46.

Roch-Lefèvre S, Mandina T, Voisin P, Gaëtan G, Mesa JEG, Valente M, et al. Quantification of gamma-H2AX foci in human lymphocytes: a method for biological dosimetry after ionizing radiation exposure. Radiat Res. 2010;174:185–94.CrossRefPubMed

47.

Beels L, Bacher K, Smeets P, Verstraete K, Vral A, Thierens H. Dose-length product of scanners correlates with DNA damage in patients undergoing contrast CT. Eur J Radiol. 2012;81:1495–9.CrossRefPubMed

48.

Rothkamm K, Horn S, Scherthan H, Rößler U, De Amicis A, Barnard S, et al. Laboratory intercomparison on the γ-H2AX foci assay. Radiat Res. 2013;180:149–55.CrossRefPubMed

49.

Hänscheid H, Lassmann M, Luster M, Thomas SR, Pacini F, Ceccarelli C, et al. Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med. 2006;47:648–54.PubMed

50.

Sandström M, Velikyan I, Garske-Román U, Sörensen J, Eriksson B, Granberg D, et al. Comparative biodistribution and radiation dosimetry of ⁶⁸Ga-DOTATOC and ⁶⁸Ga-DOTATATE in patients with neuroendocrine tumors. J Nucl Med. 2013;54:1755–9.

51.

Hänscheid H, Fernández M, Eberlein U, Lassmann M. Self-irradiation of the blood from selected nuclides in nuclear medicine. Phys Med Biol. 2014;59:1515–31.CrossRefPubMed

52.

Hänscheid H, Fernández M, Lassmann M. The absorbed dose to blood from blood-borne activity. Phys Med Biol. 2015;60:741–53.CrossRefPubMed

53.

Djuzenova CS, Elsner I, Katzer A, Worschech E, Distel LV, Flentje M, et al. Radiosensitivity in breast cancer assessed by the histone γ-H2AX and 53BP1 foci. Radiat Oncol Lond Engl. 2013;8:98.CrossRef

54.

Kroeber J, Wenger B, Schwegler M, Daniel C, Schmidt M, Djuzenova CS, et al. Distinct increased outliers among 136 rectal cancer patients assessed by γH2AX. Radiat Oncol Lond Engl. 2015;10:344.

Title: DNA damage in blood lymphocytes in patients after 177Lu peptide receptor radionuclide therapy
Authors: Uta Eberlein
Carina Nowak
Christina Bluemel
Andreas Konrad Buck
Rudolf Alexander Werner
Harry Scherthan
Michael Lassmann
Publication date: 01-10-2015
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 11/2015
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-015-3083-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 11/2015

iROLL: does 3-D radioguided occult lesion localization improve surgical management in early-stage breast cancer?

Positron emission tomography of tumour [18F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Why New Journals? The Growth of the EJNMMI Family

First-in-human evaluation of a hybrid modality that allows combined radio- and (near-infrared) fluorescence tracing during surgery

PET imaging of DNA damage using 89Zr-labelled anti-γH2AX-TAT immunoconjugates

Erratum to: First-in-human evaluation of a hybrid modality that allows combined radio- and (near-infrared) fluorescence tracing during surgery