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镭内照射后外周血单个核细胞中α粒子诱导的 DNA 损伤修复。

Repair of α-particle-induced DNA damage in peripheral blood mononuclear cells after internal ex vivo irradiation with Ra.

机构信息

Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany.

Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich, Germany.

出版信息

Eur J Nucl Med Mol Imaging. 2022 Oct;49(12):3981-3988. doi: 10.1007/s00259-022-05860-3. Epub 2022 Jun 27.


DOI:10.1007/s00259-022-05860-3
PMID:35759008
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9525426/
Abstract

PURPOSE: As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [Ra]RaCl. METHODS: Blood samples of ten volunteers were irradiated by adding [Ra]RaCl solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. RESULTS: For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h for 25 mGy, (0.16 ± 0.04) h for 50 mGy and (0.13 ± 0.02) h for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. CONCLUSION: The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.

摘要

目的:由于放射性药物疗法的α-发射器通过静脉内注射全身给药,因此血液将受到诱导双链 DNA 断裂(DSB)的α-粒子照射。在这里,我们研究了外周血单核细胞(PBMC)中 DSB 损伤的诱导和修复,作为内部离体照射后血液吸收剂量的函数[Ra]RaCl。

方法:用不同活度浓度的[Ra]RaCl 溶液对 10 名志愿者的血液进行照射,使血液吸收剂量分别为 3 mGy、25 mGy、50 mGy 和 100 mGy。分离 PBMC,分为三份,并直接固定(d 样本)或在 4 小时或 24 小时培养后固定。免疫染色后,计数诱导的γ-H2AXα 轨迹。假设修复率 R 和不可修复损伤分数 Q,用描述α 轨迹频率随时间下降的模型来描述。

结果:对于 25 mGy、50 mGy 和 100 mGy,与基线相比,所有时间点的α-轨迹数量均显著增加。与相应的 d 样本相比,4 小时和 24 小时后α-轨迹频率显著降低。修复率 R 分别为 25 mGy(0.24±0.05)h、50 mGy(0.16±0.04)h 和 100 mGy(0.13±0.02)h,表明吸收剂量较低时修复较快,而 Q 值相似。

结论:所得结果表明,DSB 损伤的诱导和修复取决于血液的吸收剂量。修复率与低线性能量转移照射观察到的相似。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/be27d5c81352/259_2022_5860_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/bcf044f506c6/259_2022_5860_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/6e0ebb1080e2/259_2022_5860_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/be27d5c81352/259_2022_5860_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/bcf044f506c6/259_2022_5860_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/6e0ebb1080e2/259_2022_5860_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824c/9525426/be27d5c81352/259_2022_5860_Fig3_HTML.jpg

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本文引用的文献

[1]
Planar Proton Minibeam Irradiation Elicits Spatially Confined DNA Damage in a Human Epidermis Model.

Cancers (Basel). 2022-3-17

[2]
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Eur J Nucl Med Mol Imaging. 2022-4

[3]
Dosing Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity.

Eur J Nucl Med Mol Imaging. 2021-12

[4]
α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [Ra]RaCl-treated prostate cancer patients.

Eur J Nucl Med Mol Imaging. 2021-8

[5]
Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA.

Eur Urol. 2021-3

[6]
Nanostructure of Clustered DNA Damage in Leukocytes after In-Solution Irradiation with the Alpha Emitter Ra-223.

Cancers (Basel). 2019-11-26

[7]
AutoFoci, an automated high-throughput foci detection approach for analyzing low-dose DNA double-strand break repair.

Sci Rep. 2018-11-23

[8]
Correlation of the absorbed dose to the blood and DNA damage in leukocytes after internal ex-vivo irradiation of blood samples with Ra-224.

EJNMMI Res. 2018-8-6

[9]
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Sci Rep. 2018-2-2

[10]
Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control.

J Nucl Med. 2018-1-11

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