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biodistribution of the agent within cells and organs, and the time course of radiation delivery determined by the radionuclide’ s physical decay and tissue clearance kinetics( Denoyer et al., 2015; Khazaei Monfared et al., 2023; Purnami et al., 2023). The use of gamma-H2AX as a biomarker of toxicity and biodosimeter following radiopharmaceutical administration is mainly based on research on 131I treatment in thyroid cancer patients and 18F-FDG PET / CT imaging( Vinnikov and Belyakov, 2022). The studies identified gamma-H2AX as a biomarker for DNA damage following internal irradiation. Validating the use of gamma-H2AX for specific radiopharmaceuticals is necessary due to the correlation between the chemical form of the radiopharmaceutical and the energy of the beta particles, which affects the proportion of DNA single-strand breaks( DSBs)( Mahmoud et al., 2022; Willers et al., 2015).
3.5 Gamma-H2AX for predicting the radiosensitivity
Irradiation leads to three distinct cell death pathways: mitotic death, apoptosis, and senescence, all contributing to the global inactivation of clonogenic potential. Mitotic death causes the development of permanently damaged chromosomal fragments( micronuclei), which are expelled from the nucleus. It is the most common kind of radiation-induced death in proliferative cells. The quantity of remaining micronuclei has been associated with radiation-induced clonogenic inactivation( Ferlazzo et al., 2017; Lobachevsky et al., 2016).
Senescence leads to a persistent and irreversible stop in the G1 phase. The most common cause of mortality for inactive cells due to radiation-induced damage is seen, particularly for doses over 4 Gy. CDKN1A / p21 expression is a dependable indicator of senescence. CDKN1A / p21 expression was shown to be dramatically decreased in radiosensitive breast cancer patients after irradiation( Ferlazzo et al., 2017; Huang and Zhou, 2020). Meanwhile, apoptosis is one of the most welldocumented pathways of cell death, although it is one of the rarest. Apoptosis mainly occurs in lymphocytes and is quite rare in fibroblasts( Derlin et al., 2021; Ferlazzo et al., 2017; Fu et al., 2023).
Unrepaired DSB appears to be the most significant endpoint for radiosensitivity among all DNA damage, given that unrepaired DSB is the primary cause of micronuclei and unrepaired chromosome breaks, and diseases associated with DSB repair defects are systematically linked to radiosensitivity( Khazaei Monfared et al., 2023; Srivastava et al., 2009). It was demonstrated that the Ataxia Telangiectasia Mutated( ATMdependent phosphorylation) of the variant histone H2AX phosphorylated on serine 139( gamma-H2AX) was among the earliest radiation-induced events by its immunofluorescence quantification of discrete nuclear foci( Srivastava et al., 2009).
Nonhomologous end-joining( NHEJ), the primary DSB repair and signalling route in mammals, recognizes DSBs via developing gamma-H2AX foci. The gamma-H2AX assay determines each radiation-induced DSB using a one-to-one connection between radiation-induced DSB and gamma- H2AX foci. In human fibroblasts, the number of unrepaired DSBs measured by the gamma-H2AX assay typically varies from 0-12 after 2 Gy and 24 hours for repair( Huang and Zhou, 2020; Purnami et al., 2023).
The generated gamma-H2AX foci may indicate the degree of DNA damage caused by radiation exposure. It is often employed in research to investigate individual radiosensitivity, since changes in cell response to radiation may be found between people( Berthel et al., 2019; Lobachevsky et al., 2016; Widjaja et al., 2022). Some persons may have a more incredible baseline amount of gamma-H2AX foci formation, suggesting heightened DNA damage sensitivity. Radiosensitivity is linked to DSB repair defects, but not all are. The challenge lies in predicting intermediate radiation responses( Huang and Zhou, 2020).
4 Conclusion
This review gives further information on the efficacy of the gamma-H2AX biomarker in determining individual radiosensitivity in cancer patients receiving radiopharmaceutical treatment. Based on the two articles analyzed, it can be concluded that the gamma-H2AX foci marker in peripheral blood cells of radiopharmaceutical therapy patients is promising for predicting treatment response and individual radiosensitivity but requires validation with more patients. In addition, it is necessary to consider the optimal time for sampling. Sampling timing significantly affects biodosimetry data accuracy, especially for high and low radiation doses. High doses may allow DNA repair early, while low doses require later sampling to observe significant changes in gH2AX foci. Analysis at this time provides more accurate information on cellular DNA damage and individual biological responses.
Acknowledgments
The authors would like to thank the Grant of Ministry of Education, Culture, Research, and Technology 2024.
Funding
This research did not receive any specific funding.
Conflicts of interest
The authors declare that they have no conflict of interest.
Data availability statement
The research data associated with this article are included within the article.
Author contribution statement
T. Kisnanto: Conceptualization, methodology, investigation, and writing the original draft. D. Ramadhani: Conceptualization, methodology, and reviewing. E. H Purwaningsih: Conceptualization, methodology, and investigation. R. W Hakim: Methodology and investigation. I. K. H Basri: Methodology and investigation. T. S Humani: Investigation and reviewing. H. N. E Surniyantoro: Investigation and reviewing. M. Syaifudin: Reviewing S. Purnami: