Radiotoxicity of an 125 I-Labeled DNA Intercalator in Mammalian Cells

Kassis, Amin I.; Fayad, Fahed; Kinsey, Berma M.; Sastry, K.S.R.; Adelstein, S. James

doi:10.2307/3577443

Cited by 71 publications

(35 citation statements)

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“…Furthermore, there is a sharp and significant drop in the energy absorbed per unit volume as a function of increasing distance from the 125 I decay site (4,9). Accordingly, the radiobiological response to Auger-electron radiation is highly sensitive to the site of decay within the cell and its proximity to nuclear DNA (9)(10)(11)(12)(13)(14)(15)(16)(17).…”

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confidence: 99%

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

et al. 2006

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Previously, the kinetics of strand break production by (125)I-labeled m-iodo-p-ethoxyHoechst 33342 ((125)IEH) in supercoiled (SC) plasmid DNA had demonstrated that approximately 1 DSB is produced per (125)I decay both in the presence and absence of the hydroxyl radical scavenger DMSO. In these experiments, an (125)IEH:DNA molar ratio of 42:1 was used. We now hypothesize that this DSB yield (but not the SSB yield) may be an overestimate due to subsequent decays occurring in any of the 41 (125)IEH molecules still bound to nicked (N) DNA. To test our hypothesis, (125)IEH was incubated with SC pUC19 plasmids ((125)IEH:DNA ratio of approximately 3:1) and the SSB and DSB yields were quantified after the decay of (125)I. As predicted, the number of DSBs produced per (125)I decay is one-half that reported previously ( approximately 0.5 compared to approximately 1, +/- DMSO) whereas the number of SSBs ( approximately 3/(125)I decay) is similar to that obtained previously ( approximately 90% are generated by OH radicals). Direct visualization by atomic force microscopy confirms formation of L and N DNA after (125)IEH decays in SC DNA and supports the strand break yields reported. These findings indicate that although SSB production is independent of the number of (125)IEH bound to DNA, the DSB yield can be augmented erroneously by (125)I decays occurring in N DNA. Further analysis indicates that 17% of SSBs and 100% of DSBs take place within the plasmid molecule in which an (125)IEH molecule decays, whereas 83% of SSBs are formed in neighboring plasmid DNA molecules.

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Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

et al. 2006

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“…Nevertheless, we compared the biological effectiveness of each compound, which we defined as the ratio of the activities of 99m Tc-HYNIC-DAPI versus 99m TcO 4 − that caused the same effect. Based on this definition, the biological effectiveness increased by approximately 4-fold in inducing SSBs and by approximately 10-fold in inducing DSBs, which is in the range reported for Auger electrons emitted in close proximity to DNA [20].…”

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confidence: 81%

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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“…The MNT-transported iodine-125 was 3500 times more cytotoxic to A431 human epidermoid carcinoma cells than [ 125 I]-iodinated control polypeptide incapable of penetrating the cells (Slastnikova et al, 2012b). Cytotoxicity of [ 125 I]-IdU expressed as N 37 , in decays per nucleus, can be used as a point of reference: i.e., as a maximum achievable cytotoxic efficiency of 125 I because [ 125 I]-IdU incorporates into DNA and its decays occur in it (Kassis et al, 1989). For Chinese hamster V79 lung fibroblasts, N 37 is equal to 120 decays per cell nucleus (Kassis et al, 1989) and was obtained under the same experimental conditions utilized by Slastnikova et al (2012b) for determining the cytotoxicity of [ 125 I]-MNT on A431 cells.…”

Section: Modular Nanotransporters: In Vitro Delivery Of Auger Electromentioning

confidence: 99%

Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

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2018

Front. Pharmacol.

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This review describes artificial modular nanotransporters (MNTs) delivering their cargos into target cells and then into the nuclei – the most vulnerable cell compartment for most anticancer agents and especially for radionuclides emitting short-range particles. The MNT strategy uses natural subcellular transport processes inherent in practically all cells including cancer cells. The MNTs use these processes just as a passenger who purchased tickets for a multiple-transfer trip making use of different kinds of public transport to reach the desired destination. The MNTs are fusion polypeptides consisting of several parts, replaceable modules, accomplishing binding to a specific receptor on the cell and subsequent internalization, endosomal escape and transport into the cell nucleus. Radionuclides emitting short-range particles, like Auger electron emitters, acquire cell specificity and significantly higher cytotoxicity both in vitro and in vivo when delivered by the MNTs into the nuclei of cancer cells. MNT modules are interchangeable, allowing replacement of receptor recognition modules, which permits their use for different types of cancer cells and, as a cocktail of several MNTs, for targeting several tumor-specific molecules for personalized medicine.

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Radiotoxicity of an 125 I-Labeled DNA Intercalator in Mammalian Cells

Cited by 71 publications

References 19 publications

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

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

Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

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Radiotoxicity of an 125 I-Labeled DNA Intercalator in Mammalian Cells

Cited by 71 publications

References 19 publications

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of125I-Hoechst

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of125I-Hoechst

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

Modular Nanotransporters for Nuclear-Targeted Delivery of Auger Electron Emitters

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Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst

Mechanisms Underlying Production of Double-Strand Breaks in Plasmid DNA after Decay of¹²⁵I-Hoechst