The quality of DNA double-strand breaks: A Monte Carlo simulation of the end-structure of strand breaks produced by protons and alpha particles

Ottolenghi, A.; Merzagora, M.; Tallone, L.; Durante, Marco; Paretzke, H. G.; Wilson, W.B.

doi:10.1007/bf01209749

Cited by 67 publications

(33 citation statements)

References 26 publications

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“…The "biological dose" has been defined as the average number of "Complex Lesions" (CLs) per cell. CLs, which are clustered breaks of the DNA double helix, have been operatively defined and calculated basing on radiation trackstructure simulations at the nm level [6]. Importantly, the beam Relative Biological Effectiveness (RBE) was found to be 1.2 along most of the SOBP (except for an increase in the peak distal part), consistent with the constant value of 1.1 adopted in therapeutic practice with protons.…”

Section: Effects At the Level Of Organs And Organism: Examples Of Calmentioning

confidence: 59%

“…The main assumption of our model [15][16][17] consists of considering chromosome aberrations as the "evolution" of clustered DNA breaks or "Complex Lesions" (CLs), which have been operationally defined as "at least two breaks in each of the two DNA strands within 30 base-pairs" [6]. Regardless of the definition, which is necessary to get quantitative simulation results, the key point is that these lesions are clustered, and thus severe and difficult to be processed by the cell repair machinery.…”

Section: Induction Of Chromosome Aberrations By Ionizing Radiationmentioning

confidence: 99%

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Modelling the radiation action for the estimation of biological effects in humans

Ballarini

Garzelli

Givone

et al. 2007

Nd2007

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Abstract.It is well known that ionizing radiation can induce biological effects at different levels, from DNA, chromosomes and cells up to tissues, organs and entire organisms. Theoretical models and Monte Carlo codes, especially those based on radiation track structure, can be of great help to elucidate the underlying mechanisms and to perform reliable predictions where data are lacking. In this work we will present and discuss a mechanistic ab initio model and a Monte Carlo code able to simulate the induction of chromosome aberrations (CAs) in human cells. This endpoint is particularly relevant, since some aberration types can lead to cell death, while others can lead to cell conversion to malignancy. The model is based on the hypothesis that only clustered lesions (CLs) of the DNA double-helix can evolve into aberrations. Simulated dose-response curves for CAs induced by different radiation types (including heavy ions) will be shown, together with applications to cancer risk estimation and biodosimetry. In this framework, we will also discuss examples of medical applications -including astronauts' exposure to space radiation -obtained with the FLUKA code, also taking into account the role of nuclear interactions.

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Section: Effects At the Level Of Organs And Organism: Examples Of Calmentioning

confidence: 59%

Section: Induction Of Chromosome Aberrations By Ionizing Radiationmentioning

confidence: 99%

Modelling the radiation action for the estimation of biological effects in humans

Ballarini

Garzelli

Givone

et al. 2007

Nd2007

Self Cite

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“…However, the damage so created could be relatively simple to repair if the number of bonds broken in the same area is not high. Hence even though a DNA molecule may undergo typically 50-100 ''breakages'' during the passage of a single light ion [8] it can still survive the ordeal intact enough to reproduce itself.…”

Section: Introductionmentioning

confidence: 99%

Comparison of protons, carbon and fullerene impacts on a carbon cylinder

Webb

Wilson

2003

Nuclear Instruments and Methods in Physics Research Section B:

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The use of protons in radiation treatment has been much studied and is widely used in the treatment of cancer cells. The proton causes damage to the strands of DNA in the cells largely by interaction with the electronic system. The proton interactions largely result in bond breakage in the DNA molecules. Sometimes the resulting damage to the DNA molecule is insufficient to cause both strands of the molecule to be broken and consequently the cell can reproduce despite being irradiated. Heavy ion therapy using carbon ions has been used to try and introduce more damage into the molecule structure, ensuring that both strands of the DNA are broken and hence preventing the cell from replicating. However, it seems that even the use of ions as heavy as carbon still result in DNA that is not fully damaged.The simulations reported here form a preliminary investigation on the possible use of a molecular species to deliver multiple impacting particles to the molecular structure thereby increasing the energy density of the impacts and thereby concentrating the damaging process to ensure the DNA molecule will be completely broken.The DNA molecule itself is a very difficult molecule to simulate in a full many body molecular dynamics simulation environment and in this conceptual study we approximate the DNA molecule by a set of carbon discs and investigate the difference between the impacts of protons, carbon atoms and fullerene molecules on an elongated strong of carbon discs. The cylinder used has a similar atom density and radius to DNA and the equilibrium disc separation is very similar to the separation distance of the individual nucleotides found in DNA, consequently this much simpler system might be considered to be a reasonable starting point for a thought experiment to see if there are any potential advantages in using molecular or cluster species in this form of treatment.

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“…The assumption of a major role of clustered -and thus severe -DNA damage, already adopted by Sachs and Brenner (1993), mainly relies on that while "simple" DSBs do not show significant dependence on radiation quality, clustered breaks increase with the radiation LET and depend on the radiation type (Ottolenghi et al, 1995;Nikjoo et al, 1997). This is consistent with the LET-and particle-type dependence found in experiments on gene mutation and cell killing (Belli et al, 1992).…”

Section: Assumptionsmentioning

confidence: 99%

“…Goodhead, 1994). In our model such damage was quantified by introducing the so-called "Complex Lesions", which in a previous work (Ottolenghi et al, 1995) have been operationally defined as "at least two single-strand breaks on each of the two DNA strands within 30 base pairs" and have been calculated for different radiation types with an "event-by-event" track structure code. The hypothesis of a major role of Complex Lesions is supported by previous works in which CLs have been assumed to lead to clonogenic cell inactivation (Ottolenghi et al, 1997;Biaggi et al, 1999).…”

Section: Assumptionsmentioning

confidence: 99%

Models of chromosome aberration induction: an example based on radiation track structure

Ballarini

Ottolenghi²

2004

Cytogenet Genome Res

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A few examples of models of chromosome aberration induction are summarised and discussed on the basis of the three main theories of aberration formation, that is “breakage-and-reunion”, “exchange” and “one-hit”. A model and code developed at the Universities of Milan and Pavia is then presented in detail. The model provides dose-response curves for different aberration types (dicentrics, translocations, rings, complex exchanges and deletions) induced in human lymphocytes by gamma rays, protons and alpha particles of different energies, both as monochromatic fields and as mixed fields. The main assumptions are that only clustered – and thus severe – DNA breaks (“Complex Lesions”, CL) can participate in the production of aberrations, and that only break free ends in neighbouring chromosome territories can interact and form exchanges. The yields of CLs induced by the various radiation types of interest are taken from a previous modelling work. These lesions are distributed within a sphere representing the cell nucleus according to the radiation track structure, e.g. randomly for gamma rays and along straight lines for light ions. Interphase chromosome territories are explicitly simulated and configurations are obtained in which each chromosome occupies an intranuclear domain with volume proportional to its DNA content. In order to allow direct comparisons with experimental data, small fragments can be neglected since usually they cannot be detected in experiments. The presence of a background level of aberrations is also taken into account. The results of the simulations are in good agreement with experimental dose-response curves available in the literature, that provides a validation of the model both in terms of the adopted assumptions and in terms of the simulation techniques. To address the question of “true” incompleteness, simulations were also run in which all fragments were assumed to be visible.

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The quality of DNA double-strand breaks: A Monte Carlo simulation of the end-structure of strand breaks produced by protons and alpha particles

Cited by 67 publications

References 26 publications

Modelling the radiation action for the estimation of biological effects in humans

Modelling the radiation action for the estimation of biological effects in humans

Comparison of protons, carbon and fullerene impacts on a carbon cylinder

Models of chromosome aberration induction: an example based on radiation track structure

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