Abstract
The aim of this study was to build a simulation framework to evaluate the number of DNA double-strand breaks (DSBs) induced by invitro targeted radionuclide therapy (TRT). This work represents the first step toward exploring underlying biologic mechanisms and the influence of physical and chemical parameters to enable a better response prediction in patients. We used this tool to characterize early DSB induction by 177Lu-DOTATATE, a commonly used TRT for neuroendocrine tumors. Methods: A multiscale approach was implemented to simulate the number of DSBs produced over 4 h by the cumulated decays of 177Lu distributed according to the somatostatin receptor binding. The approach involves 2 sequential simulations performed with Geant4/Geant4-DNA. The radioactive source is sampled according to uptake experiments on the distribution of activities within the medium and the planar cellular cluster, assuming instant and permanent internalization. A phase space is scored around the nucleus of the central cell. Then, the phase space is used to generate particles entering the nucleus containing a multiscale description of the DNA in order to score the number of DSBs per particle source. The final DSB computations are compared with experimental data, measured by immunofluorescent detection of p53-binding protein 1 foci. Results: The probability of electrons reaching the nucleus was significantly influenced by the shape of the cell compartment, causing a large variance in the induction pattern of DSBs. A significant difference was found in the DSBs induced by activity distributions in cell and medium, as is explained by the specific energy ([Formula: see text]) distributions. The average number of simulated DSBs was 14 DSBs per cell (range, 7-24 DSBs per cell), compared with 13 DSBs per cell (range, 2-30 DSBs per cell) experimentally determined. We found a linear correlation between the mean absorbed dose to the nucleus and the number of DSBs per cell: 0.014 DSBs per cell mGy-1 for internalization in the Golgi apparatus and 0.017 DSBs per cell mGy-1 for internalization in the cytoplasm. Conclusion: This simulation tool can lead to a more reliable absorbed-dose-to-DNA correlation and help in prediction of biologic response.
Highlights
The most common way of exposing cancer patients to radiation is through external beam radiotherapy (EBRT)
A significant difference was found in the double strand breaks (DSBs) induced by activity distributions in cell and medium, which is explained by the specific energy (z) distributions
We found a linear correlation between the mean absorbed dose to the nucleus and the number of DSBs/cell: 0.014 DSBs/cell mGy-1 for internalization in the Golgi apparatus and 0.017 DSBs/cell mGy-1 for internalization in the cytoplasm
Summary
The most common way of exposing cancer patients to radiation is through external beam radiotherapy (EBRT). The success and effectiveness of EBRT can, at least partially, be attributed to the knowledge of its radiobiological principles and their integration into dose-response modelling [1]. TRT is based on the injection of a radiolabeled molecule which has the advantage of targeting specific cancer cells, enabling the delivery of a cytotoxic absorbed dose to eradicate both a primary tumor site and metastases [2]. In striking contrast to EBRT, TRT is marked by the scarcity of radiobiological investigations and dose-response modelling. The physical characteristics of TRT, i.e. heterogeneous radiation caused by variable uptake at cellular and subcellular level, protracted exposure causing overlapped biological mechanisms such as DNA damage formation and repair and low dose-rate, differ significantly from EBRT, TRT-specific radiobiological knowledge and biophysical modelling need to be developed [3]
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