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  • Title: In vivo formation of gamma-H2AX and 53BP1 DNA repair foci in blood cells after radioiodine therapy of differentiated thyroid cancer.
    Author: Lassmann M, Hänscheid H, Gassen D, Biko J, Meineke V, Reiners C, Scherthan H.
    Journal: J Nucl Med; 2010 Aug; 51(8):1318-25. PubMed ID: 20660387.
    Abstract:
    UNLABELLED: DNA double-strand breaks (DSBs) are critical cellular lesions that can result from ionizing radiation exposure. A marker for DSB formation is the phosphorylated form of the histone H2 variant H2AX (gamma-H2AX). DSBs also attract the damage sensor p53-binding protein 1 (53BP1) to the DSB-containing chromatin, because 53BP1 associates with the DSB-surrounding chromatin. We studied the induction, persistence, and disappearance of radiation-induced gamma-H2AX and 53BP1 foci after the first (131)I therapy of patients with differentiated thyroid carcinoma, a model for protracted, continuous, internal whole-body irradiation. METHODS: Twenty-six patients (7 men, 19 women; mean age +/- SD, 42 +/- 13 y) underwent posttherapeutic blood dosimetry according to the standard operating procedure of the European Association of Nuclear Medicine, including peripheral blood sampling and external dose rate measurements at 2-144 h after administration of (131)I for thyroid remnant ablation. The mean time curves of dose accumulation and dose rate to the blood were compared with the mean gamma-H2AX and 53BP1 foci counts over the same period in samples of mononuclear peripheral blood leukocytes. RESULTS: The mean absorbed dose to the blood in 24 patients evaluable for physical dosimetry was 0.31 +/- 0.10 Gy (minimum, 0.17 Gy; maximum, 0.57 Gy). After 24 h, the mean daily dose increment was less than 0.05 Gy. The excess focus counts per nucleus--that is, nuclear foci in excess of the low background count--peaked at 2 h after radioiodine administration (median excess foci for gamma-H2AX [n = 21 patients], 0.227, and for 53BP1 [n = 19 patients], 0.235) and progressively declined thereafter. Significantly elevated numbers of excess focus counts per nucleus (median excess foci for gamma-H2AX [n = 8 patients], 0.054, and for 53BP1 [n = 6 patients], 0.046) still were present at 120-144 h after therapy. Because the rate of occurrence of radiation-induced focus counts per nucleus per absorbed dose varied considerably among patients, a dose-response relationship could not be established for this series as a whole. The number of excess radiation-induced focus counts per nucleus per absorbed dose rate increased with time, potentially indicating a slower rate of DNA repair or, alternatively, a higher de novo rate of focus formation. The values over time of both radiation-induced DSB markers correlated closely (r(2) = 0.973). CONCLUSION: Radiation-induced gamma-H2AX and 53BP1 nuclear foci are useful markers for detecting radiation exposure after radionuclide incorporation, even for absorbed doses to the blood below 20 mGy.
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