Abstract
Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.
Highlights
About 5–10% of the patients treated with radiotherapy show early and/or severe side reactions of the co-irradiated normal tissue without any indication for predispositions like previous diseases or exogenous factors [1]
Using the parameters tested here lymphoblastoid cell lines (LCLs) do not reflect the physiological properties of the corresponding peripheral blood lymphocytes (PBLs) with regard to ionizing radiation (IR)-induced apoptosis measured with the Annexin V test
This study was initiated to validate cellular parameters derived from patient cells for their capacity to predict the radiosensitivity of patients’ co-irradiated normal tissue
Summary
About 5–10% of the patients treated with radiotherapy show early and/or severe side reactions of the co-irradiated normal tissue without any indication for predispositions like previous diseases or exogenous factors [1]. Five different laboratories investigated in parallel different radiobiological endpoints in identical aliquots of encoded primary peripheral blood lymphocytes (PBLs) and derived EBV-transformed lymphoblastoid cell lines (LCLs) of matched sample pairs from clinically radiosensitive vs normal responding tumour patients and 15 lymphoblastoid cell lines from age- and sex-matched healthy controls of the KORA study. Acute grade 2 reaction below 20 Gy or acute grade 3 reaction on the breast Using these criteria, 15 patients (10 breast carcinomas, 5 head and neck carcinomas) displaying acute clinical radiation hypersensitivity were available at the beginning of this study without a tumour recurrence or secondary malignancy. Sample preparation and management as well as EBV-transformation were described previously [12]
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