DNA lesions correlate with lymphocyte function after selective internal radiotherapy
- 18 Downloads
In patients with non-resectable hepatic malignancies selective internal radiotherapy (SIRT) with yttrium-90 is an effective therapy. However, previous data indicate that SIRT leads to impaired immune function. The aim of the current study was to determine the extent of DNA lesions in peripheral blood mononuclear cells of SIRT patients and to correlate these lesions with cellular immune responses. In ten patients γH2AX and 53BP1 foci were determined. These foci are markers of DNA double-strand breaks (DSBs) and occur consecutively. In parallel, lymphocyte proliferation was assessed after stimulation with the T cell mitogen phytohemagglutinin. Analyses of vital cells were performed prior to and 1 h and 1 week after SIRT. 1 h and 1 week after SIRT numbers of γH2AX and of 53BP1 foci were more than threefold larger than before (p < 0.01). Already at baseline, foci were more abundant than published in healthy controls. Lymphocyte proliferation at baseline was below the normal range and further decreased after SIRT. Prior to therapy, there was an inverse correlation between lymphocyte proliferation and the quotient 53BP1/γH2AX; which could be considered as a measure of the course of DNA DSB repair (r = − 0.94, p < 0.0001). Proliferative responses were inversely correlated with 53BP1 foci prior to therapy and γH2AX and 53BP1 foci 1 h after therapy (r < − 0.65, p < 0.05). In conclusion, DNA foci in SIRT patients were correlated with impaired in vitro immune function. Unrepaired DNA DSBs or cell cycle arrest due to repair may cause this impairment.
KeywordsSelective internal radiotherapy DNA double strand break DNA repair Cellular immune response Lymphocyte proliferation ELISpot
Double strand break
Lymphocyte transformation test
Protein histone 2A family member X
Selective internal radiotherapy
Tumor suppressor p53-binding protein 1
γH2AX and 53PB1 immunofluorescence stainings were kindly performed free of charge by Caroline Eberle, Lisa Heiserich and Peter Bauer (Medipan, Berlin, Germany). This article is a partial fulfilment of requirements for the doctor’s degree at the Medical Faculty, University of Duisburg-Essen, for Aglaia Domouchtsidou. The authors would like to thank Monika Huben and Martina Praast for their excellent technical assistance.
ML, VB, SPM, PL, AD, PAH and AB contributed to the conception and design of the study. AD and JB recruited the patients and took blood samples. AD performed the cellular in vitro assays. AD, PL and ML wrote the report. All authors critically revised and approved the final manuscript.
No relevant funding.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval and ethical standards
The study was institutional review board approved by the ethics committee of the Medical Faculty, University Hospital Essen (approval number 09-3991), and carried out in accordance with the 1964 Helsinki Declaration.
All participants provided written informed consent prior to their inclusion in the study.
- 18.Zwicker F, Swartman B, Sterzing F, Major G, Weber KJ, Huber PE, Thieke C, Debus J, Herfarth K (2011) Biological in-vivo measurement of dose distribution in patients’ lymphocytes by gamma-H2AX immunofluorescence staining: 3D conformal- vs. step-and-shoot IMRT of the prostate gland. Radiat Oncol 6:62CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Buchali A, Heiserich L, Bauer P, Tregel M, Roggenbuck D, Franzen A (2017) Baseline H2AX foci, 53BP1 values and late morbidity after definitive radio-chemotherapy in head and neck carcinoma patients. J Solid Tumors 7(1):11–15Google Scholar
- 25.Goutham HV, Mumbrekar KD, Vadhiraja BM, Fernandes DJ, Sharan K, Kanive Parashiva G, Kapaettu S, Bola Sadashiva SR (2012) DNA double-strand break analysis by gamma-H2AX foci: a useful method for determining the overreactors to radiation-induced acute reactions among head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 84(5):e607–e612CrossRefPubMedGoogle Scholar
- 31.Joubert-Huebner E Kap. 6. Leber. Anatomie und Physiologie. The European Board of Cardiovascular Perfusion. http://www.kardiotechnik.org/kap_06.pdf. Accessed 8 Jan 2019