INT . J . RADIAT . BIOL ., VOL .
62,
NO .
1, 9-20
Model of DNA damage induced by radiations of various qualities V. MICHALIK*t
Int J Radiat Biol Downloaded from informahealthcare.com by UB der LMU Muenchen on 02/21/13 For personal use only.
(Received 30 May 1991 ; revision received 27 August 1991 ; accepted 8 September 1991)
Abstract. A theoretical model permitting estimation of yields of various DNA damages induced by radiations of varying qualities is described . It is based on the Monte-Carlo track structure simulation and DNA structure, and links physical, physicochemical and chemical stages of radiation action . Direct and indirect effects are not strictly distinguished but treated cooperatively. Good agreement between calculated and measured initial yields of double-strand breaks was observed . Other multiple and single damages of DNA are studied . When radiation quality is changed there are quantitative and qualitative transitions in the damage spectrum . The proportion of multiple damage in the damage spectrum is about 30% for low-LET radiations and increases considerably with increasing ionization density.
1. Introduction Extensive studies of the biological action of radiation at the cellular level have placed the DNA molecule at the top in the hierarchy of possible targets . Reproductive cell death, mutation and transformation are closely related to molecular damage in DNA . After irradiation of the cell there is a broad spectrum of radiation-induced damages which can eventually lead to the different endpoints . The understanding of mechanisms of biological action of radiation requires identification of individual molecular damages and determination of their significance for various final effects . A useful tool in these investigations is the employment of radiations of varying quality because their initial damage spectra are different . Experimental assays are only available for measurement of some types of damage (particularly strand breaks), whereas others cannot be measured . In this case models of radiation damage in DNA can give at least a qualitative insight as to the yields of such damages and their dependence on radiation quality . The approach presented here comes from a knowledge of radiation track structure and the structure *Division of Biophysics, Joint Institute for Nuclear Research, Dubna . PO Box 79, 101 000, USSR t Present address : Institute of Radiation Dosimetry. Na Truhlarce 39/64, Prague 8, 180 86, Czechoslovakia .
of DNA. The result of superimposition of these structures is the primary physical DNA damage which is transformed during the physicochemical and chemical processes that follow . At these stages the effect of reactive radicals induced in the close surroundings of DNA is taken into account, and cooperative action of direct DNA ionizations and 'OH radicals is considered . The result is initial DNA molecular lesions which can be considered to be one of the crucial factors determining the resulting cellular state after irradiation. In the literature several approaches to the simulation of yields of DNA damages induced by varying quality radiations can be found . Most of these theoretical models concentrate on strand breakage . Calculations of yields of strand breaks, distinguishing the contributions of track core and penumbra, were performed by Obaturov (1979) . Kozubek and Krasavin (1984) based their calculations on the radial dose distribution concept . Giinther and Schulz (1983) introduced a model based on microdosimetry where the track structure and yields of DNA strand breaks are linked together by a set of free parameters matched to the experimental data . Other authors started with Monte-Carlo track structure simulations . Charlton and Humm (1988) calculated DNA strand breaks induced by the decay of incorporated 1251 and extended their calculations later to other radiations (Charlton et al. 1989), Goodhead and Nikjoo (1989) correlated frequencies of energy deposition in target volume with dimensions comparable to short segments of DNA with induction frequency of double-strand breaks (dsb) . All these calculations consider the particle track structure but neglect subsequent levels of radiation action . 'OH radicals are taken into account by Ito (1987), who calculated yields of dsb for electrons of various energies, and his calculation is based on the proximity function concept. Chatterjee and Holley (1990a), and Holley et al. (1990) built a model of DNA damage for high-LET particles based on the analytical track structure, considering direct as well as indirect DNA damage .
0020-7616/92 $3.00 © 1992 Taylor & Francis Ltd
10
V. Michalik
Int J Radiat Biol Downloaded from informahealthcare.com by UB der LMU Muenchen on 02/21/13 For personal use only.
2 . Track structure Ionizing radiation differs from other DNA damaging agents by its ability to produce clusters of adjacent damages over distances of a few manometers. Characterization of radiation track structure reflecting this critical property could be suitable for the calculations of yields of DNA lesions . The comprehensive information about the spatial distribution of energy deposited was obtained by MonteCarlo simulation of particle tracks . Charged particle tracks in water vapour with unit density were generated by the program written by Lappa et al. (1989) . The spatial distribution of ionizations was analysed by the K-means method (Spath 1980) used for the classification of objects and allowing partitioning of the track structure into clusters of ionizations . Using this clustering algorithm we can compute an absolute frequency distribution of clusters h(j) . This distribution h(j) is always defined for the concrete cluster parameterp limiting the spatial dimensions of a cluster . A cluster of the order j can be understood as a domain in space containing j ionizations when the distance between any of two ionizations belonging to the same cluster is
62,
NO .
1, 9-20
Model of DNA damage induced by radiations of various qualities V. MICHALIK*t
Int J Radiat Biol Downloaded from informahealthcare.com by UB der LMU Muenchen on 02/21/13 For personal use only.
(Received 30 May 1991 ; revision received 27 August 1991 ; accepted 8 September 1991)
Abstract. A theoretical model permitting estimation of yields of various DNA damages induced by radiations of varying qualities is described . It is based on the Monte-Carlo track structure simulation and DNA structure, and links physical, physicochemical and chemical stages of radiation action . Direct and indirect effects are not strictly distinguished but treated cooperatively. Good agreement between calculated and measured initial yields of double-strand breaks was observed . Other multiple and single damages of DNA are studied . When radiation quality is changed there are quantitative and qualitative transitions in the damage spectrum . The proportion of multiple damage in the damage spectrum is about 30% for low-LET radiations and increases considerably with increasing ionization density.
1. Introduction Extensive studies of the biological action of radiation at the cellular level have placed the DNA molecule at the top in the hierarchy of possible targets . Reproductive cell death, mutation and transformation are closely related to molecular damage in DNA . After irradiation of the cell there is a broad spectrum of radiation-induced damages which can eventually lead to the different endpoints . The understanding of mechanisms of biological action of radiation requires identification of individual molecular damages and determination of their significance for various final effects . A useful tool in these investigations is the employment of radiations of varying quality because their initial damage spectra are different . Experimental assays are only available for measurement of some types of damage (particularly strand breaks), whereas others cannot be measured . In this case models of radiation damage in DNA can give at least a qualitative insight as to the yields of such damages and their dependence on radiation quality . The approach presented here comes from a knowledge of radiation track structure and the structure *Division of Biophysics, Joint Institute for Nuclear Research, Dubna . PO Box 79, 101 000, USSR t Present address : Institute of Radiation Dosimetry. Na Truhlarce 39/64, Prague 8, 180 86, Czechoslovakia .
of DNA. The result of superimposition of these structures is the primary physical DNA damage which is transformed during the physicochemical and chemical processes that follow . At these stages the effect of reactive radicals induced in the close surroundings of DNA is taken into account, and cooperative action of direct DNA ionizations and 'OH radicals is considered . The result is initial DNA molecular lesions which can be considered to be one of the crucial factors determining the resulting cellular state after irradiation. In the literature several approaches to the simulation of yields of DNA damages induced by varying quality radiations can be found . Most of these theoretical models concentrate on strand breakage . Calculations of yields of strand breaks, distinguishing the contributions of track core and penumbra, were performed by Obaturov (1979) . Kozubek and Krasavin (1984) based their calculations on the radial dose distribution concept . Giinther and Schulz (1983) introduced a model based on microdosimetry where the track structure and yields of DNA strand breaks are linked together by a set of free parameters matched to the experimental data . Other authors started with Monte-Carlo track structure simulations . Charlton and Humm (1988) calculated DNA strand breaks induced by the decay of incorporated 1251 and extended their calculations later to other radiations (Charlton et al. 1989), Goodhead and Nikjoo (1989) correlated frequencies of energy deposition in target volume with dimensions comparable to short segments of DNA with induction frequency of double-strand breaks (dsb) . All these calculations consider the particle track structure but neglect subsequent levels of radiation action . 'OH radicals are taken into account by Ito (1987), who calculated yields of dsb for electrons of various energies, and his calculation is based on the proximity function concept. Chatterjee and Holley (1990a), and Holley et al. (1990) built a model of DNA damage for high-LET particles based on the analytical track structure, considering direct as well as indirect DNA damage .
0020-7616/92 $3.00 © 1992 Taylor & Francis Ltd
10
V. Michalik
Int J Radiat Biol Downloaded from informahealthcare.com by UB der LMU Muenchen on 02/21/13 For personal use only.
2 . Track structure Ionizing radiation differs from other DNA damaging agents by its ability to produce clusters of adjacent damages over distances of a few manometers. Characterization of radiation track structure reflecting this critical property could be suitable for the calculations of yields of DNA lesions . The comprehensive information about the spatial distribution of energy deposited was obtained by MonteCarlo simulation of particle tracks . Charged particle tracks in water vapour with unit density were generated by the program written by Lappa et al. (1989) . The spatial distribution of ionizations was analysed by the K-means method (Spath 1980) used for the classification of objects and allowing partitioning of the track structure into clusters of ionizations . Using this clustering algorithm we can compute an absolute frequency distribution of clusters h(j) . This distribution h(j) is always defined for the concrete cluster parameterp limiting the spatial dimensions of a cluster . A cluster of the order j can be understood as a domain in space containing j ionizations when the distance between any of two ionizations belonging to the same cluster is
