Model assembly for estimating cell surviving fraction for both targeted and nontargeted effects based on microdosimetric probability densities

ミクロ線量の確率密度分布に基づく標的・非標的効果を同時に考慮可能な細胞生存率評価モデル集合体

佐藤 達彦   ; 浜田 信行*

Sato, Tatsuhiko; Hamada, Nobuyuki*

様々な線種の電離放射線に照射された細胞の生存率について、標的効果と非標的効果の双方を考慮して推定可能な新たなモデルを開発した。放射線場を特徴づけるための指標として、従来のモデルでよく使われてきたマクロ吸収線量やLETではなく、各細胞核及びその内部構造(ドメイン)におけるミクロ吸収線量の確率密度分布を用いた。これらの確率密度分布は、粒子・重イオン輸送計算コードPHITSにより計算可能である。標的効果の表現には、以前に確立したDSMK(二重確率論的マイクロドジメトリ動態)モデルを用い、非標的効果の表現には新たなモデルを開発した。開発したモデルの妥当性を調べるため、様々な細胞腫や照射条件に対する生存率について、その生物実験データとモデル計算データを比較した。その結果、モデル計算は広範囲の線量とLETについて生物実験データをよく再現することが示された。標的効果、非標的効果、Bcl-2過剰発現の効果を考慮したこの新たなモデルは、重粒子線治療、密封小線源治療、ホウ素中性子捕獲療法など、様々な先進医療の治療成績と有害事象の評価精度向上に役立つと期待できる。

We here propose a new model assembly for estimating the surviving fraction of cells irradiated with various types of ionizing radiation, considering both targeted and nontargeted effects in the same framework. The probability densities of specific energies in cell nucleus and domain calculated by PHITS were employed as the physical index for characterizing the radiation fields. In the model assembly, our previously established double stochastic microdosimetric kinetic (DSMK) model was used to express the targeted effect, whereas a newly developed model was used to express the nontargeted effect. The radioresistance caused by overexpression of anti-apoptotic protein Bcl-2 known to frequently occur in human cancer was also considered by introducing the concept of the adaptive response in the DSMK model. The accuracy of the model assembly was examined by comparing the computationally and experimentally determined surviving fraction of Bcl-2 and Neo cells irradiated with microbeam or broadbeam of energetic heavy ions, as well as the WI-38 normal human fibroblasts irradiated with X-ray microbeam. The model assembly reproduced very well the experimentally determined surviving fraction over a wide range of dose and linear energy transfer (LET) values. Our newly established model assembly will be worth being incorporated into treatment planning systems for heavy-ion therapy, brachytherapy, and boron neutron capture therapy, given critical roles of the frequent Bcl-2 overexpression and the nontargeted effect in estimating therapeutic outcomes and harmful effects of such advanced therapeutic modalities.