Model Assembly for Estimating Cell Surviving Fraction for Both Targeted and Nontargeted Effects Based on Microdosimetric Probability Densities

Abstract

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 two scales, which are the cell nucleus and its substructure called a domain, 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 cells (Bcl-2 overexpressing HeLa cells) and Neo cells (neomycin resistant gene-expressing HeLa 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.

Microdosimetric Modeling of Biological Effectiveness for Boron Neutron Capture Therapy Considering Intra- and Intercellular Heterogeneity in 10B Distribution

“…This is why the double stochastic microdosimetric kinetic (DSMK) model 11 , which can handle the saturation correction more precisely but with longer computational time, was not employed in this study. Taken together, the SMK and DSMK models have a function to deal with the nontargeted effects 25 , but this function is not used in this study because the nontargeted effects play only a negligible role in cell inactivation at high-dose irradiation where estimation of the therapeutic effect is important.…”

Effect of dose-delivery time for flattened and flattening filter-free photon beams based on microdosimetric kinetic model

“…The measurement point was located at a 10 cm depth in the water-equivalent phantom material. The dose-mean lineal energy y D [ 24 – 26 ] was calculated as: where ε , l , f ( y ), and d ( y ) are the energy deposited in a domain, mean chord length, probability density of the lineal energy, and dose distribution of the lineal energy, respectively.…”

Analysis of the high-dose-range radioresistance of prostate cancer cells, including cancer stem cells, based on a stochastic model

“…Several cell-killing models considering radiosensitive factors (such as microdosimetry, dose-rate effects and intercellular communication) have been proposed for providing the relationship between absorbed dose and cell survival [16–22]. Among these, a trial for modeling cell-killing in multicell populations was also performed [20, 21], indicating that some modifications of the dose–response curve were required. However, the relationship between measured CSC contents and the cell survival curve described by the model has not been quantified yet.…”