Reduction in clonogenic survival of sodium-iodide symporter (NIS)-positive cells following intracellular uptake of<sup>99m</sup>Tc versus<sup>188</sup>Re

Freudenberg, Robert; Wendisch, M.; Runge, Roswitha; Wunderlich, Gerd; Kotzerke, Jörg

doi:10.3109/09553002.2012.728303

Cited by 12 publications

(15 citation statements)

References 28 publications

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“…The salivary gland dataset demonstrates that the biological events triggered by 99m TcO 4 − exposure happen selectively in NIS-expressing cells capable of accumulating the radiotracer. The requirement for 99m TcO 4 − to enter the cell in order to provoke maximal DNA damage and, if the dose is high enough, cell death, has been demonstrated in vitro using the NIS-expressing PCCl3 thyroid cell line [45], [46], [47], [48]. In these experiments, 99m TcO 4 − -mediated toxicity was clearly magnified by 99m TcO 4 − entry into the cells [45], [46], [47] and was further enhanced by 99m TcO 4 − retention [48].…”

Section: Discussionmentioning

confidence: 99%

“…The requirement for 99m TcO 4 − to enter the cell in order to provoke maximal DNA damage and, if the dose is high enough, cell death, has been demonstrated in vitro using the NIS-expressing PCCl3 thyroid cell line [45], [46], [47], [48]. In these experiments, 99m TcO 4 − -mediated toxicity was clearly magnified by 99m TcO 4 − entry into the cells [45], [46], [47] and was further enhanced by 99m TcO 4 − retention [48]. This increased radiotoxicity from intracellular 99m Tc is likely to be the result of an increased dose deposition in cellular structures due to Auger and conversion electrons, with low range and high local energy deposition properties.…”

Section: Discussionmentioning

confidence: 99%

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99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

et al. 2014

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Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, 99mTc, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4 −) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4 − required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4 −–mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by 99mTc can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

et al. 2014

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“…The latter activities were estimated to yield a cellular dose of 1 Gy from extracellular irradiation. All uptake studies were performed at 37 • C and as described by Haberkorn et al, 7 van Sande et al, 8 and Meller et al 9 Briefly, for each break point and both activity concentrations of 99m Tc and 123 I, parallel cell cultures were incubated for 15 and 30 min and for 1,2,4,6,8,12,16,20, and 24 h. After being washed twice with ice-cold PBS, the cells were detached using accutase. The radioactivities of the supernatants, wash solutions, and cell lysates were measured using an automated gamma counter (Cobra II, Autogamma, Packard R , Canberra Company, Rüsselsheim, Germany).…”

Section: D Uptake and Efflux Quantificationmentioning

confidence: 99%

“…In previous studies, we examined the therapeutic potential of 99m Tc compared with prominent therapeutic radionuclides such as 131 I (Ref. 3) and 188 Re, 4 as well as in comparison with the alpha emitter 211 At. 5 In this study, we evaluated the clonogenic cell survival under the influence of 99m Tc compared with the well-known Auger emitter 123 I.…”

Section: Introductionmentioning

confidence: 99%

On the dose calculation at the cellular level and its implications for the RBE of^99mTc and¹²³I

et al. 2014

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The authors' data indicate that extra-nuclear targets to Auger electrons exist, which is obvious from our dose calculations. When considering the dose to the cell nucleus, the authors found an enhanced RBE for(99m)Tc and (123)I relative to acute x-ray irradiation and pure extracellular irradiation with both radionuclides. Surprisingly, the authors did not find any radionuclide accumulation in the cell nucleus, indicating that there are additional radiosensitive targets besides the DNA. In addition, the authors demonstrated the necessity of cellular dose calculations in radiobiological experiments using unsealed radionuclides and identified the relevant parameters.

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“…Kotzerke et al compared the uptake of 99m Tc versus 211 At in NIS-positive rat thyroid cells [8], Wendisch et al investigated the clonogenic survival after intracellular uptake of 99m Tc vs. 131 I [9], whereas Freudenberg et al compared 99m Tc to 188 Re. [10]. Because nuclear uptake was negligible, DNA damage by low-energy Auger electrons could not be detected.…”

Section: Introductionmentioning

confidence: 99%

99mTc-Labeled HYNIC-DAPI Causes Plasmid DNA Damage with High Efficiency

et al. 2014

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99mTc is the standard radionuclide used for nuclear medicine imaging. In addition to gamma irradiation, 99mTc emits low-energy Auger and conversion electrons that deposit their energy within nanometers of the decay site. To study the potential for DNA damage, direct DNA binding is required. Plasmid DNA enables the investigation of the unprotected interactions between molecules and DNA that result in single-strand breaks (SSBs) or double-strand breaks (DSBs); the resulting DNA fragments can be separated by gel electrophoresis and quantified by fluorescent staining. This study aimed to compare the plasmid DNA damage potential of a 99mTc-labeled HYNIC-DAPI compound with that of 99mTc pertechnetate (99mTcO4 −). pUC19 plasmid DNA was irradiated for 2 or 24 hours. Direct and radical-induced DNA damage were evaluated in the presence or absence of the radical scavenger DMSO. For both compounds, an increase in applied activity enhanced plasmid DNA damage, which was evidenced by an increase in the open circular and linear DNA fractions and a reduction in the supercoiled DNA fraction. The number of SSBs elicited by 99mTc-HYNIC-DAPI (1.03) was twice that caused by 99mTcO4 − (0.51), and the number of DSBs increased fivefold in the 99mTc-HYNIC-DAPI-treated sample compared with the 99mTcO4 − treated sample (0.02 to 0.10). In the presence of DMSO, the numbers of SSBs and DSBs decreased to 0.03 and 0.00, respectively, in the 99mTcO4 – treated samples, whereas the numbers of SSBs and DSBs were slightly reduced to 0.95 and 0.06, respectively, in the 99mTc-HYNIC-DAPI-treated samples. These results indicated that 99mTc-HYNIC-DAPI induced SSBs and DSBs via a direct interaction of the 99mTc-labeled compound with DNA. In contrast to these results, 99mTcO4 − induced SSBs via radical formation, and DSBs were formed by two nearby SSBs. The biological effectiveness of 99mTc-HYNIC-DAPI increased by approximately 4-fold in terms of inducing SSBs and by approximately 10-fold in terms of inducing DSBs.

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Reduction in clonogenic survival of sodium-iodide symporter (NIS)-positive cells following intracellular uptake of^99mTc versus¹⁸⁸Re

Cited by 12 publications

References 28 publications

99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

On the dose calculation at the cellular level and its implications for the RBE of^99mTc and¹²³I

99mTc-Labeled HYNIC-DAPI Causes Plasmid DNA Damage with High Efficiency

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Reduction in clonogenic survival of sodium-iodide symporter (NIS)-positive cells following intracellular uptake of99mTc versus188Re

Cited by 12 publications

References 28 publications

99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

99mTcO4−-, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events

On the dose calculation at the cellular level and its implications for the RBE of99mTc and123I

99mTc-Labeled HYNIC-DAPI Causes Plasmid DNA Damage with High Efficiency

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Reduction in clonogenic survival of sodium-iodide symporter (NIS)-positive cells following intracellular uptake of^99mTc versus¹⁸⁸Re

On the dose calculation at the cellular level and its implications for the RBE of^99mTc and¹²³I