The Paradoxical Nature of DNA Damage and Cell Death Induced by 125 I Decay

Hofer, Kurt G.; Loon, Nanette van; Schneiderman, Marvin A.; Charlton, D.E.

doi:10.2307/3578489

Cited by 30 publications

(4 citation statements)

References 9 publications

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“…For the 125 I, Geselowits et al (50) quantified the toxicity of radiation of the [ 125 I]IUdR incorporated in the nucleus of CHO cells in the early S phase. The result was a D 37 between 40 and 165 decays/cell of 125 I, which is consistent with the work of Hofer et al (52) who reported a mean value of ~100 decays/ cell. On the other hand, Humm and Charlton (29) derived the following relationship between the total number of DSB (N DSB ) and the initial number of radioactive atoms (N 0 ) attached to DNA base pairs (and hence the activity) which are needed to produce such DSB, as follows:…”

Section: Initial Activity Of 64 Cu To Cause Lethal Damagesupporting

confidence: 92%

Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods

Carrasco-Hernandez,

Ramos-Méndez,

Padilla-Rodal

et al. 2023

Front. Med.

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PurposeTargeted Radionuclide Therapy (TRT) with Auger Emitters (AE) is a technique that allows targeting specific sites on tumor cells using radionuclides. The toxicity of AE is critically dependent on its proximity to the DNA. The aim of this study is to quantify the DNA damage and radiotherapeutic potential of the promising AE radionuclide copper-64 (64Cu) incorporated into the DNA of mammalian cells using Monte Carlo track-structure simulations.MethodsA mammalian cell nucleus model with a diameter of 9.3 μm available in TOPAS-nBio was used. The cellular nucleus consisted of double-helix DNA geometrical model of 2.3 nm diameter surrounded by a hydration shell with a thickness of 0.16 nm, organized in 46 chromosomes giving a total of 6.08 giga base-pairs (DNA density of 14.4 Mbp/μm3). The cellular nucleus was irradiated with monoenergetic electrons and radiation emissions from several radionuclides including 111In, 125I, 123I, and 99mTc in addition to 64Cu. For monoenergetic electrons, isotropic point sources randomly distributed within the nucleus were modeled. The radionuclides were incorporated in randomly chosen DNA base pairs at two positions near to the central axis of the double-helix DNA model at (1) 0.25 nm off the central axis and (2) at the periphery of the DNA (1.15 nm off the central axis). For all the radionuclides except for 99mTc, the complete physical decay process was explicitly simulated. For 99mTc only total electron spectrum from published data was used. The DNA Double Strand Breaks (DSB) yield per decay from direct and indirect actions were quantified. Results obtained for monoenergetic electrons and radionuclides 111In, 125I, 123I, and 99mTc were compared with measured and calculated data from the literature for verification purposes. The DSB yields per decay incorporated in DNA for 64Cu are first reported in this work. The therapeutic effect of 64Cu (activity that led 37% cell survival after two cell divisions) was determined in terms of the number of atoms incorporated into the nucleus that would lead to the same DSBs that 100 decays of 125I. Simulations were run until a 2% statistical uncertainty (1 standard deviation) was achieved.ResultsThe behavior of DSBs as a function of the energy for monoenergetic electrons was consistent with published data, the DSBs increased with the energy until it reached a maximum value near 500 eV followed by a continuous decrement. For 64Cu, when incorporated in the genome at evaluated positions (1) and (2), the DSB were 0.171 ± 0.003 and 0.190 ± 0.003 DSB/decay, respectively. The number of initial atoms incorporated into the genome (per cell) for 64Cu that would cause a therapeutic effect was estimated as 3,107 ± 28, that corresponds to an initial activity of 47.1 ± 0.4 × 10−3 Bq.ConclusionOur results showed that TRT with 64Cu has comparable therapeutic effects in cells as that of TRT with radionuclides currently used in clinical practice.

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Section: Initial Activity Of 64 Cu To Cause Lethal Damagesupporting

confidence: 92%

Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods

Carrasco-Hernandez,

Ramos-Méndez,

Padilla-Rodal

et al. 2023

Front. Med.

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“…Examples of track structure analysis and applications have been proposed by Nikjoo [198]. In this context, the extension of microdosimetry to energy deposition in small volumes of some tens of nm may be relevant since damage to higher order structures than molecular DNA could contribute to and perhaps be required for cell killing [192]. Finally, a phenomenological approach combining microdosimetric distributions with biological response functions (see 2.2) is not restricted to µm simulated biological targets.…”

Section: Energy Deposition In Cells By Short-range Electronsmentioning

confidence: 99%

“…One reason for considering a mechanistic approach, i.e. one involving elementary physical and if possible molecular processes, is the observation of an unexpected type of DNA damage, which cannot be classically interpreted as high-or low-LET damage even when Auger-emitters are incorporated into DNA [192].…”

Section: Energy Deposition In Cells By Short-range Electronsmentioning

confidence: 99%

Dosimetry and Microdosimetry of Targeted Radiotherapy

Bardiès

Pihet²

2000

CPD

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Dosimetry in targeted radiotherapy (TR) uses different calculation methods, whose degree of refinement is closely conditioned by the particular objective sought. It is more generally performed to establish a correlation between the quantity of radiation delivered to a target and the biological damage observed or that can be reliably predicted. It can thus be used to optimise treatments and allow comparison of different therapeutic approaches, as well as to study the basic methods of irradiation of biological matter. Two broad types of investigations can be found in the literature: microdosimetric ones (stochastic approaches used to study energy deposits) and macrodosimetric ones (non-stochastic or deterministic approaches). The mathematical formalism is consistent between these two types, and the calculation methods currently used are often similar. This review presents different approaches to the dosimetry of radionuclides used in TR. The introduction defines the general problem, the role of dosimetry in TR and the specific problems raised by targeting (non-uniformity of source distributions). The first part considers the types of calculation methods found in TR in relation to the basic quantities used to represent stochastic energy deposit on a cellular scale. In particular, it compares the formalism and the methods used in microdosimetric or conventional macrodosimetric approches. Although microdosimetry, or even track structure calculations, can provide the basic elements for modelling the absorbed dose process, a simplified dosimetric approach may be adequate to describe the phenomena observed. The scheme proposed by the MIRD committee relates to such an approach and is presented together with other methods allowing the calculation of the mean dose delivered (analytic methods, dose point kernels, Monte-Carlo, etc.). The second part shows the application range for the various methods, providing selected examples of dosimetric approaches in TR on different scales, from the organ (or tissues) to the cell or even DNA, and a brief presentation of bone marrow dosimetry.

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“…There are strong grounds for critical evaluation of both the track physics model and conventional risk models. A recent paper by Hofer et al [17] suggests that cell death is associated with higher order structures in the cell nucleus than DNA segments. This may alter perspectives in some conventional risk models.…”

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confidence: 99%

On the Linear Extrapolation to Low Doses

Katz¹,

Waligorski²

1994

Radiation Protection Dosimetry

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IntroductionThe linear quadratic model is widely used in radiobiology to fit data of limited dynamic range, nominally not greater than two decades in dose, and at doses in the neighborhood of grays as summarized in NCRP report No. 104 [1]. This model has only qualitative and rhetorical support, in the form of statements about one track and two track effects, as justifying the linear and the quadratic components, respectively, and ignores the statistical fluctuation of track intersections with targets, especially important in the limit of low doses. There is no quantitative theoretical base for such a model other than the assertion that electron track ends might act like high LET radiations, a qualified appraisal at best, unsupported by direct experimental evidence, though frequently inferred from energy deposited in small volumes which approximate small sections of DNA at track ends by stopping electrons, or from the number of ionizations therein, both from Monte Carlo calculations. The relation between the linear quadratic formula and the theory of dual radiation action [2] is noted, but it must be pointed out that it is the experimental fit of the linear quadratic formula to data which supports the theory of dual radiation action, rather than the converse. Quoting Kellerer "Concepts of microdosimetry are, of course, essential in any analysis of the action of ionizing radiation on the cell. Their employment has led to important insights but not, as yet, to a quantitative treatment of the primary cellular changes" [3]. It is widely recognized that the linear quadratic formula fails outside its fitted range. Linear Extrapolation to Low Doses of Low LET RadiationsIn NCRP Report 104 [1], observations of biological effects with low LET radiations are extrapolated linearly to doses of 1 mGy and below in order to evaluate the RBE of high LET radiations at low doses. However, a flux of relativistic electrons at which single electrons pass through cells deposits a dose in the neighborhood of 1 mGy. It may be asked, do single electron transits through cells kill, mutate, transform mammalian cells? Do single electron transits induce cancers? It must be kept in mind that the extrapolation involved is substantial, as much as three or four orders of magnitude, frequently from grays to milligrays. But the extrapolation is not only quantitative. It is qualitative as well, pressing on the very validity of the concept of dose. Is there any basic reason why dose, an amorphous concept used to characterise a chaotic distribution of secondary electrons which experience has proven adequate as a plotting parameter when thousands of electrons from orthovoltage X rays or gamma rays traverse cells, should also be valid when single electrons traverse cells, and when the statistical consideration invoked in target theory is ignored? Experimental DataSeveral of the following citations have already been noted [4].Cole et al. [5] have found that some 500 electrons pass into the nucleus of a CHO cell, on average, for inactivation. 52:1-4 (1994...

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The Paradoxical Nature of DNA Damage and Cell Death Induced by 125 I Decay

Cited by 30 publications

References 9 publications

Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods

Cellular lethal damage of 64Cu incorporated in mammalian genome evaluated with Monte Carlo methods

Dosimetry and Microdosimetry of Targeted Radiotherapy

On the Linear Extrapolation to Low Doses

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