Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

Open Access 01-07-2019 | Prostate Cancer | Original Article

DNA damage in blood leucocytes of prostate cancer patients during therapy with ¹⁷⁷Lu-PSMA

Authors: Sarah Schumann, Harry Scherthan, Constantin Lapa, Sebastian Serfling, Razan Muhtadi, Michael Lassmann, Uta Eberlein

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 8/2019

Abstract

Purpose

The aim of this study was to investigate the time- and dose-dependency of DNA double-strand break (DSB) induction and repair in peripheral blood leucocytes of prostate cancer patients during therapy with ¹⁷⁷Lu-PSMA.

Methods

Blood samples from 16 prostate cancer patients receiving their first ¹⁷⁷Lu-PSMA therapy were taken before and at seven time-points (between 1 h and 96 h) after radionuclide administration. Absorbed doses to the blood were calculated using integrated time–activity curves of the blood and the whole-body. For DSB quantification, leucocytes were isolated, fixed in ethanol and immunostained with γ-H2AX and 53BP1 antibodies. Colocalizing foci of both DSB markers were manually counted in a fluorescence microscope.

Results

The average number of radiation-induced foci (RIF) per cell increased within the first 4 h after administration, followed by a decrease indicating DNA repair. The number of RIF during the first 2.6 h correlated linearly with the absorbed dose to the blood (R² = 0.58), in good agreement with previously published in-vitro data. At late time-points (48 h and 96 h after administration), the number of RIF correlated linearly with the absorbed dose rate (R² = 0.56). In most patients, DNA DSBs were repaired effectively. However, in some patients RIF did not disappear completely even 96 h after administration.

Conclusion

The general pattern of the time- and dose-dependent induction and disappearance of RIF during ¹⁷⁷Lu-PSMA therapy is similar to that of other radionuclide therapies.

Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004;91(3):528–39. https://doi.org/10.1002/jcb.10661.CrossRefPubMed

Sweat SD, Pacelli A, Murphy GP, Bostwick DG. Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology. 1998;52(4):637–40.CrossRefPubMed

Ahmadzadehfar H, Rahbar K, Kurpig S, Bogemann M, Claesener M, Eppard E, et al. Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. EJNMMI Res. 2015;5:36. https://doi.org/10.1186/s13550-015-0114-2.CrossRefPubMedCentral

Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schafers M, Essler M, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58(1):85–90. https://doi.org/10.2967/jnumed.116.183194.CrossRefPubMed

Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825–33. https://doi.org/10.1016/S1470-2045(18)30198-0.CrossRefPubMed

Kratochwil C, Giesel FL, Stefanova M, Benesova M, Bronzel M, Afshar-Oromieh A, et al. PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with 177Lu-labeled PSMA-617. J Nucl Med. 2016;57(8):1170–6. https://doi.org/10.2967/jnumed.115.171397.CrossRefPubMed

Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, et al. 177Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. J Nucl Med. 2016;57(7):1006–13. https://doi.org/10.2967/jnumed.115.168443.CrossRefPubMed

Kulkarni HR, Singh A, Schuchardt C, Niepsch K, Sayeg M, Leshch Y, et al. PSMA-based radioligand therapy for metastatic castration-resistant prostate cancer: the Bad Berka experience since 2013. J Nucl Med. 2016;57(Suppl 3):97S–104S. https://doi.org/10.2967/jnumed.115.170167.CrossRefPubMed

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(8):1318–25. https://doi.org/10.2967/jnumed.109.071357.CrossRefPubMed

10.

Rogakou EP, Boon C, Redon C, Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 1999;146(5):905–16.CrossRefPubMedPubMedCentral

11.

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(10):5858–68.CrossRefPubMed

12.

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(7):1381–90.CrossRefPubMedPubMedCentral

13.

Chowdhury D, Keogh MC, Ishii H, Peterson CL, Buratowski S, Lieberman J. Gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell. 2005;20(5):801–9. https://doi.org/10.1016/j.molcel.2005.10.003.CrossRefPubMed

14.

Eberlein U, Nowak C, Bluemel C, Buck AK, Werner RA, Scherthan H, et al. DNA damage in blood lymphocytes in patients after (177)Lu peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2015;42(11):1739–49. https://doi.org/10.1007/s00259-015-3083-9.CrossRefPubMedPubMedCentral

15.

Eberlein U, Scherthan H, Bluemel C, Peper M, Lapa C, Buck AK, et al. DNA damage in peripheral blood lymphocytes of thyroid cancer patients after radioiodine therapy. J Nucl Med. 2016;57(2):173–9. https://doi.org/10.2967/jnumed.115.164814.CrossRefPubMed

16.

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(9):5057–62. https://doi.org/10.1073/pnas.0830918100.CrossRefPubMedPubMedCentral

17.

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 gamma-H2AX foci of DNA damage in lymphocytes. Ann Nucl Med. 2013;27(3):233–8. https://doi.org/10.1007/s12149-012-0678-0.CrossRefPubMed

18.

Denoyer D, Lobachevsky P, Jackson P, Thompson M, Martin OA, Hicks RJ. Analysis of 177Lu-DOTA-octreotate therapy-induced DNA damage in peripheral blood lymphocytes of patients with neuroendocrine tumors. J Nucl Med. 2015;56(4):505–11. https://doi.org/10.2967/jnumed.114.145581.CrossRefPubMed

19.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMed

20.

Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122S–50S. https://doi.org/10.2967/jnumed.108.057307.CrossRefPubMed

21.

Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402–18. https://doi.org/10.1200/JCO.2015.64.2702.CrossRefPubMedPubMedCentral

22.

Eberlein U, Peper M, Fernandez M, Lassmann M, Scherthan H. Calibration of the gamma-H2AX DNA double strand break focus assay for internal radiation exposure of blood lymphocytes. PLoS One. 2015;10(4):e0123174. https://doi.org/10.1371/journal.pone.0123174.CrossRefPubMedPubMedCentral

23.

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(2):e87458. https://doi.org/10.1371/journal.pone.0087458.CrossRefPubMedPubMedCentral

24.

Wilkins RC, Wilkinson D, Maharaj HP, Bellier PV, Cybulski MB, McLean JR. Differential apoptotic response to ionising radiation in subpopulations of human white blood cells. Mutat Res. 2002;513(1-2):27–36.CrossRefPubMed

25.

Horn S, Barnard S, Brady D, Prise KM, Rothkamm K. Combined analysis of gamma-H2AX/53BP1 foci and caspase activation in lymphocyte subsets detects recent and more remote radiation exposures. Radiat Res. 2013;180(6):603–9. https://doi.org/10.1667/RR13342.1.CrossRefPubMed

Title: DNA damage in blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA
Authors: Sarah Schumann
Harry Scherthan
Constantin Lapa
Sebastian Serfling
Razan Muhtadi
Michael Lassmann
Uta Eberlein
Publication date: 01-07-2019
Publisher: Springer Berlin Heidelberg
Keywords: Prostate Cancer
Addiction
Prostate Cancer
Addiction
Radionuclide Therapy
Enzalutamide
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 8/2019
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-019-04317-4

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

DNA damage in blood leucocytes of prostate cancer patients during therapy with ¹⁷⁷Lu-PSMA

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 8/2019

Role of 18F-FLT PET/CT in suspected recurrent or residual lymphoma: final results of a pilot prospective trial

Prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with combined hepatocellular-cholangiocarcinoma

Small-voxel reconstructions significantly influence SUVs in PET imaging

Treatment of brain metastases of castration-resistant prostate cancer with 225Ac-PSMA-617

Re-evaluation of the diagnostic performance of 11C-methionine PET/CT according to the 2016 WHO classification of cerebral gliomas

Diffusion-weighted MRI and 18F-FDG PET correlation with immunity in early radiotherapy response in BNL hepatocellular carcinoma mouse model: timeline validation