Ritsuko Watanabe

Biological Dose Estimation for Charged-Particle Therapy Using an Improved PHITS Code Coupled with a Microdosimetric Kinetic Model

Abstract Sato, T., Kase, Y., Watanabe, R., Niita, K. and Sihver, L. Biological Dose Estimation for Charged Particle Therapy Using an Improved PHITS Code Coupled with a Microdosimetric Kinetic Model. Radiat. Res. 171, 107–117 (2009). Microdosimetric quantities such as lineal energy, y, are better indexes for expressing the RBE of HZE particles in comparison to LET. However, the use of microdosimetric quantities in computational dosimetry is severely limited because of the difficulty in calculating their probability densities in macroscopic matter. We therefore improved the particle transport simulation code PHITS, providing it with the capability of estimating the microdosimetric probability densities in a macroscopic framework by incorporating a mathematical function that can instantaneously calculate the probability densities around the trajectory of HZE particles with a precision equivalent to that of a microscopic track-structure simulation. A new method for estimating biological dose, the product of physical dose and RBE, from charged-particle therapy was established using the improved PHITS coupled with a microdosimetric kinetic model. The accuracy of the biological dose estimated by this method was tested by comparing the calculated physical doses and RBE values with the corresponding data measured in a slab phantom irradiated with several kinds of HZE particles. The simulation technique established in this study will help to optimize the treatment planning of charged-particle therapy, thereby maximizing the therapeutic effect on tumors while minimizing unintended harmful effects on surrounding normal tissues.

Visualisation of γH2AX Foci Caused by Heavy Ion Particle Traversal; Distinction between Core Track versus Non-Track Damage

Heavy particle irradiation produces complex DNA double strand breaks (DSBs) which can arise from primary ionisation events within the particle trajectory. Additionally, secondary electrons, termed delta-electrons, which have a range of distributions can create low linear energy transfer (LET) damage within but also distant from the track. DNA damage by delta-electrons distant from the track has not previously been carefully characterised. Using imaging with deconvolution, we show that at 8 hours after exposure to Fe (∼200 keV/µm) ions, γH2AX foci forming at DSBs within the particle track are large and encompass multiple smaller and closely localised foci, which we designate as clustered γH2AX foci. These foci are repaired with slow kinetics by DNA non-homologous end-joining (NHEJ) in G1 phase with the magnitude of complexity diminishing with time. These clustered foci (containing 10 or more individual foci) represent a signature of DSBs caused by high LET heavy particle radiation. We also identified simple γH2AX foci distant from the track, which resemble those arising after X-ray exposure, which we attribute to low LET delta-electron induced DSBs. They are rapidly repaired by NHEJ. Clustered γH2AX foci induced by heavy particle radiation cause prolonged checkpoint arrest compared to simple γH2AX foci following X-irradiation. However, mitotic entry was observed when ∼10 clustered foci remain. Thus, cells can progress into mitosis with multiple clusters of DSBs following the traversal of a heavy particle.

Oxidation yield of the ferrous ion in a Fricke solution irradiated with monochromatic synchrotron soft X-rays in the 1.8-10 keV region

The oxidation yield of ferrous ion in a Fricke solution was measured in the soft X-ray region from 1.8 to 10 keV. The standard Fricke solution was irradiated with monochromatic X-rays from synchrotron radiation. The yield decreased with decreasing X-ray energy, as several theoretical calculations have predicted. No significant changes were observed in the K-shell photo-absorption of the iron and sulphur contained in the standard Fricke solution. The high-LET nature of soft X-rays is discussed.

Spectrum of Radiation-Induced Clustered Non-DSB Damage – A Monte Carlo Track Structure Modeling and Calculations

The aim of this report is to present the spectrum of initial radiation-induced cellular DNA damage [with particular focus on non-double-strand break (DSB) damage] generated by computer simulations. The radiation types modeled in this study were monoenergetic electrons (100 eV–1.5 keV), ultrasoft X-ray photons Ck, AlK and TiK, as well as some selected ions including 3.2 MeV/u proton; 0.74 and 2.4 MeV/u helium ions; 29 MeV/u nitrogen ions and 950 MeV/u iron ions. Monte Carlo track structure methods were used to simulate damage induction by these radiation types in a cell-mimetic condition from a single-track action. The simulations took into account the action of direct energy deposition events and the reaction of hydroxyl radicals on atomistic linear B-DNA segments of a few helical turns including the water of hydration. Our results permitted the following conclusions: a. The absolute levels of different types of damage [base damage, simple and complex single-strand breaks (SSBs) and DSBs] vary depending on the radiation type; b. Within each damage class, the relative proportions of simple and complex damage vary with radiation type, the latter being higher with high-LET radiations; c. Overall, for both low- and high-LET radiations, the ratios of the yields of base damage to SSBs are similar, being about 3.0 ± 0.2; d. Base damage contributes more to the complexity of both SSBs and DSBs, than additional SSB damage and this is true for both low- and high-LET radiations; and e. The average SSB/DSB ratio for low-LET radiations is about 18, which is about 5 times higher than that for high-LET radiations. The hypothesis that clustered DNA damage is more difficult for cells to repair has gained currency among radiobiologists. However, as yet, there is no direct in vivo experimental method to validate the dependence of kinetics of DNA repair on DNA damage complexity (both DSB and non-DSB types). The data on the detailed spectrum of DNA damage presented here, in particular the non-DSB type, provide a good basis for testing mechanistic models of DNA repair kinetics such as base excision repair.

Analysis of cell-survival fractions for heavy-ion irradiations based on microdosimetric kinetic model implemented in the particle and heavy ion transport code system

It is considered that the linear energy transfer (LET) may not be the ideal index for expressing the relative biological effectiveness (RBE) of cell killing for heavy-ion irradiation, as the ion-species dependencies have clearly been observed in the relation between LET and RBE derived from cell-survival fraction data. The previously measured survival fractions of four cell lines irradiated by various ion species, employing the saturation-corrected dose-mean lineal energy, y*, instead of LET as the index of the RBE were therefore re-analysed. In the analysis, the initial slopes of the survival fractions, the so-called α-parameter in the linear-quadratic model, were plotted as a function of y*, which was calculated by the microdosimetric kinetic (MK) model implemented in the Particle and Heavy Ion Transport code System. It was found from the analysis that the ion-species dependencies observed in the relations between α and LET disappeared from those between α and y*, and their relations can be well reproduced by a simple equation derived from the MK model. These results clearly indicate the suitability of y* to be used in the estimation of the RBE of cell killing for heavy-ion irradiations, which is of great importance in the treatment planning of charged-particle therapy.

Induction of DNA Strand Breaks, Base Lesions and Clustered Damage Sites in Hydrated Plasmid DNA Films by Ultrasoft X Rays around the Phosphorus K Edge

Abstract To characterize the DNA damage induced by K-shell ionization of phosphorus atom in DNA backbone on the level of hydration, the yields of DNA strand breaks and base lesions arising from the interaction of ultrasoft X rays with energies around the phosphorus K edge were determined using dry and fully hydrated pUC18 plasmid DNA samples. Base lesions and bistranded clustered DNA damage sites were revealed by postirradiation treatment with the base excision repair proteins endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg). The yield of prompt single-strand breaks (SSBs) with dry DNA irradiated at the phosphorus K resonance energy (2153 eV) is about one-third that below the phosphorus K edge (2147 eV). The yields of prompt double-strand breaks (DSBs) were found to be less dependent on the X-ray energy, with the yields being about two times lower when irradiated at 2153 eV. Heat-labile sites were not produced in detectable amounts. The yields of base lesions were dependent on the energy of the X rays, especially when the DNA was fully hydrated. Bistranded clustered DNA damage sites, revealed enzymatically as additional DSBs, were produced in dry as well as in hydrated DNA with all three energies of X rays. The yields of these enzyme-sensitive sites were also lower when irradiated at the phosphorus K resonance energy. On the other hand, the yields of prompt SSBs and enzyme-sensitive sites for the two off-resonance energies were, larger than those determined previously for γ radiation. The results indicate that the photoelectric effect caused by X rays and dense ionization and excitation events along the tracks of low-energy secondary electrons are more effective at inducing SSBs and enzyme-sensitive sites. The complex types of damage, prompt and enzymatically induced DSBs, are preferentially induced by phosphorus K resonance at 2153 eV rather than simple SSBs and isolated base lesions, particularly in hydrated conditions. It is concluded that not only the phosphorus K resonance and resulting emission of low-energy LMM-Auger electrons (∼120 eV) but also the level of hydration plays an important role in the induction of complex damage in plasmid DNA.

Monte Carlo simulation of radial distribution of DNA strand breaks along the C and Ne ion paths

Radial energy deposition distribution, the distribution of DNA strand breaks and their yields were simulated by Monte Carlo track structure simulation for C and Ne ions with the same linear energy transfer (LET) around 450 keV/μm. The radial DNA damage distribution shows different pattern for C and Ne ions. Double strand break (DSB) are mostly formed in the central area, while the single strand break (SSB) tends to spread to the surrounding area. It is also shown that the production efficiency of the SSB and DSB depends on the radial distance. This result shows reasonable agreement with the recently obtained experimental observation, which indicates that different types of DNA damage shows different distribution patterns around C and Ne ion paths in cell nuclei.

Radial dose distribution around a heavy ion's path☆

Abstract Ionization currents produced in a small wall-less ionization chamber located at varying distance from the 200 MeV Ni 12+ ions path traversing Ar gas were measured and utilized to construct a track structure model. Using the LET value of 200 MeV Ni 12+ and G (Fe 3+ ) in Fricke solutions (= 15.4) for fast electrons, we estimate G (Fe 3+ ) for 200 MeV Ni 12+ to be 5.0.

Applications of the microdosimetric function implemented in the macroscopic particle transport simulation code PHITS

Abstract Purpose: Microdosimetric quantities such as lineal energy are generally considered to be better indices than linear energy transfer (LET) for expressing the relative biological effectiveness (RBE) of high charge and energy particles. To calculate their probability densities (PD) in macroscopic matter, it is necessary to integrate microdosimetric tools such as track-structure simulation codes with macroscopic particle transport simulation codes. Methods: As an integration approach, the mathematical model for calculating the PD of microdosimetric quantities developed based on track-structure simulations was incorporated into the macroscopic particle transport simulation code PHITS (Particle and Heavy Ion Transport code System). The improved PHITS enables the PD in macroscopic matter to be calculated within a reasonable computation time, while taking their stochastic nature into account. Applications: The microdosimetric function of PHITS was applied to biological dose estimation for charged-particle therapy and risk estimation for astronauts. The former application was performed in combination with the microdosimetric kinetic model, while the latter employed the radiation quality factor expressed as a function of lineal energy. Conclusion: Owing to the unique features of the microdosimetric function, the improved PHITS has the potential to establish more sophisticated systems for radiological protection in space as well as for the treatment planning of charged-particle therapy.

Yield of Single- and Double-Strand Breaks and Nucleobase Lesions in Fully Hydrated Plasmid DNA Films Irradiated with High-LET Charged Particles

We measured the yield and spectrum of strand breaks and nucleobase lesions produced in fully hydrated plasmid DNA films to determine the linear energy transfer (LET) dependence of DNA damage induced by ion-beam irradiation in relation to the change in the atomic number of ions. The yield of isolated damage was revealed as a decrease in prompt SSBs with increasing LET of He2+, C5+,6+ and Ne8+,10+ ions. On the other hand, the yields of prompt DSBs increased with increasing ion LET. SSBs were additionally induced in ion-irradiated DNA film by treatment with two kinds of base excision repair proteins (glycosylases), Nth and Fpg, indicating that base lesions are produced in the hydrated DNA film. This result shows that nucleobase lesions are produced via both chemical reactions with diffusible water radicals, such as OH radicals, and direct energy deposition onto DNA and the hydrated water layer. Nth-sensitive sites deduced to be pyrimidine lesions, such as 5,6-dihydrothymine (DHT), showed a relatively larger yield than Fpg-sensitive sites deduced to be purine lesions, such as 7,8-dihydro-8-oxo-2′deoxyguanine (8-oxoGua), for all ion exposures tested. The yield of SSBs or DSBs observed by enzyme treatment decreased noticeably with increasing LET for all tested ions. These results indicated that higher-LET ions preferentially produce a complex type of damage that might compromise the activities of the glycosylases used in this study. These findings are biologically important since, under cell mimicking conditions, persistent DNA damage occurs in part due to direct energy deposition on the DNA or hydrated water shell that is specifically induced by dense ionization in the track.