Prediction of the Acute or Late Radiation Toxicity Effects in Radiotherapy Patients Using Ex Vivo Induced Biodosimetric Markers: A Review

Abstract

A search for effective methods for the assessment of patients’ individual response to radiation is one of the important tasks of clinical radiobiology. This review summarizes available data on the use of ex vivo cytogenetic markers, typically used for biodosimetry, for the prediction of individual clinical radiosensitivity (normal tissue toxicity, NTT) in cells of cancer patients undergoing therapeutic irradiation. In approximately 50% of the relevant reports, selected for the analysis in peer-reviewed international journals, the average ex vivo induced yield of these biodosimetric markers was higher in patients with severe reactions than in patients with a lower grade of NTT. Also, a significant correlation was sometimes found between the biodosimetric marker yield and the severity of acute or late NTT reactions at an individual level, but this observation was not unequivocally proven. A similar controversy of published results was found regarding the attempts to apply G2- and γH2AX foci assays for NTT prediction. A correlation between ex vivo cytogenetic biomarker yields and NTT occurred most frequently when chromosome aberrations (not micronuclei) were measured in lymphocytes (not fibroblasts) irradiated to relatively high doses (4–6 Gy, not 2 Gy) in patients with various grades of late (not early) radiotherapy (RT) morbidity. The limitations of existing approaches are discussed, and recommendations on the improvement of the ex vivo cytogenetic testing for NTT prediction are provided. However, the efficiency of these methods still needs to be validated in properly organized clinical trials involving large and verified patient cohorts.

Cisplatin Reduces the Frequencies of Radiotherapy-Induced Micronuclei in Peripheral Blood Lymphocytes of Patients with Gynaecological Cancer: Possible Implications for the Risk of Second Malignant Neoplasms

“…This result suggests that the variation in radiation-induced cytogenetic damage in PBL does not reflect the intrinsic radiosensitivity of a donor but is more likely influenced by environmental factors. This result fits well with the findings of others [63,66,67].…”

A 4-Gene Signature of CDKN1, FDXR, SESN1 and PCNA Radiation Biomarkers for Prediction of Patient Radiosensitivity

“…The use of PBL in donor cohorts is ideal for the development of a predictive biomarker of radiosensitivity. A recent review on ex vivo-induced biodosimetric markers to predict acute or late radiation toxicity effects in radiotherapy patients described the benefits of cytogenetic assays using PBL to help evaluate individual radiosensitivity according to dose and genetic status, because radiation-induced damage is related to altered DNA repair mechanisms and therefore cellular radiosensiviity [ 37 ]. Herein, 4 genes related to the ATM/CHK2/P53 pathway in the DNA Damage Response (DDR) were selected for this study including CDKN1A, FDXR, SESN1 and PCNA possibly directly associated with the underlying mechanisms of G2 chromosomal radiosensitivity in individual donor cohorts.…”

“…Both mRNA and chromosomes (irradiated in culture at 0.05 Gy and 0.5 Gy IR) were extracted from the same donor samples in all cohorts and used for G2 chromosomal radiosensitivity and gene expression, respectively, as different but complimentary biomarker approaches. This multiparametric approach, combined into an entire prognostic profile, might provide better discrimination for the discovery of biomarkers to eventually be adopted into clinical practice [ 37 ].…”

Transcriptional Dynamics of DNA Damage Responsive Genes in Circulating Leukocytes during Radiotherapy

“…Non-AT patients without clear clinical symptoms before the beginning of RT can also experience severe acute normal tissue toxicity reactions such as those associated with major DNA double-strand break repair deficiency [ 7 , 8 , 9 , 10 , 11 ]. The role of Ataxia-telangiectasia mutated (ATM) seems crucial [ 12 ], but biomarkers to identify patients at risk are still needed to allow for more individualised RT treatments [ 13 ]. There is still a lack of fully validated biomarkers to assess the acute and late toxicity in addition to long-term risks on an individual basis [ 14 , 15 , 16 ], particularly in the case of paediatric RT.…”