Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles.
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ABSTRACT:
SUBMITTER: Polf JC
PROVIDER: S-EPMC3170386 | biostudies-other | 2011 May
REPOSITORIES: biostudies-other
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Project description:PURPOSE:We introduce a methodology to calculate the microdosimetric quantity dose-mean lineal energy for input into the microdosimetric kinetic model (MKM) to model the relative biological effectiveness (RBE) of proton irradiation experiments. METHODS AND MATERIALS:The data from 7 individual proton RBE experiments were included in this study. In each experiment, the RBE at several points along the Bragg curve was measured. Monte Carlo simulations to calculate the lineal energy probability density function of 172 different proton energies were carried out with use of Geant4 DNA. We calculated the fluence-weighted lineal energy probability density function (fw(y)), based on the proton energy spectra calculated through Monte Carlo at each experimental depth, calculated the dose-mean lineal energy yD¯ for input into the MKM, and then computed the RBE. The radius of the domain (rd) was varied to reach the best agreement between the MKM-predicted RBE and experimental RBE. A generic RBE model as a function of dose-averaged linear energy transfer (LETD) with 1 fitting parameter was presented and fit to the experimental RBE data as well to facilitate a comparison to the MKM. RESULTS:Both the MKM and LETD-based models modeled the RBE from experiments well. Values for rd were similar to those of other cell lines under proton irradiation that were modeled with the MKM. Analysis of the performance of each model revealed that neither model was clearly superior to the other. CONCLUSIONS:Our 3 key accomplishments include the following: (1) We developed a method that uses the proton energy spectra and lineal energy distributions of those protons to calculate dose-mean lineal energy. (2) We demonstrated that our application of the MKM provides theoretical validation of proton irradiation experiments that show that RBE is significantly greater than 1.1. (3) We showed that there is no clear evidence that the MKM is better than LETD-based RBE models.
| S-EPMC6499683 | biostudies-literature
Project description:PurposeRelative biological effectiveness (RBE) accounts for the differences in biological effect from different radiation types. The RBE for proton therapy remains uncertain, as it has been shown to vary from the clinically used value of 1.1. In this work we investigated the RBE of protons and correlated the biological differences with the underlying physical quantities.Materials and methodsThree cell lines were irradiated (CHO, Chinese hamster ovary; A549, human lung adenocarcinoma; and T98, human glioma) and assessed for cell survival by using clonogenic assay. Cells were irradiated with 71- and 160-MeV protons at depths along the Bragg curve and 6-MV photons to various doses. The dose-averaged lineal energy ( y‒D ) was measured under similar conditions as the cells by using a microdosimeter. Dose-averaged linear energy transfer (LETd) was also calculated by using Monte Carlo (MC) simulations. Survival data were fit by using the linear quadratic model. The RBE values were calculated by comparing the physical dose (D6MV/Dp) that results in 50% (RBE0.5) and 10% (RBE0.1) cell survival, and survival after 2 Gy (RBE2Gy).ResultsProton RBE values ranged from 0.89 to 2.40. The RBE for all 3 cell lines increased with decreasing proton energy and was higher at 50% survival than at 10% survival. Additionally, both A549 and T98 cells generally had higher RBE values relative to the CHO cells, indicating a greater biological response to protons. An increase in RBE corresponded with an increase in y‒D and LETd.ConclusionProton RBE was found to depend on mean proton energy, survival end point, and cell type. Changes in both y‒D and LETd were also found to impact proton RBE values, but consideration of the energy spectrum may provide additional information. The RBE values in this study vary greatly, indicating the clinical value of 1.1 may not be suitable in all cases.
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Project description: Not available
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Project description:PURPOSE:Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ?1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation. METHODS AND MATERIALS:Isogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/?m) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison. RESULTS:Loss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage. CONCLUSIONS:A defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers.
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Project description:An ideal radiosensitizer holding an enhanced tumor retention can play an incredible role in enhancing tumor radiotherapy. Herein, a strategy of acid-triggered aggregation of small-sized gold nanoparticles (GNPs) system within tumor is proposed and the resulting GNPs aggregates are applied as a radiosensitizer in vitro and in vivo. The GNPs system with the acid-triggered aggregation achieves an enhanced GNPs accumulation and retention in cancer cells and tumors in the form of the resulted GNPs aggregates. As a consequence, the radiosensitization effect shows significant improvement in cancer radiotherapy, which is shown in the studies of DNA breakage and the comet assay, and the sensitizer enhancement ratio (SER) value of the GNPs system (1.730) with MCF-7 cancer cells is much larger than that of the single GNPs (1.16). In vivo antitumor studies reveal that the GNPs system also enhances the sensitivity of MCF-7 tumor xenograft to radiotherapy. Furthermore, the GNPs aggregates improve the signal of small GNPs in vivo photoacoustic imaging. This study provides a new strategy and insights into fabricating nanoaggregates to magnify the radiosensitive efficiency of nanosystems in cancer radiotherapy.
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Project description:Large amounts of high quality biophysical data are needed to improve current biological effects models but such data are lacking and difficult to obtain. The present study aimed to more efficiently measure the spatial distribution of relative biological effectiveness (RBE) of charged particle beams using a novel high-accuracy and high-throughput experimental platform. Clonogenic survival was selected as the biological endpoint for two lung cancer cell lines, H460 and H1437, irradiated with protons, carbon, and helium ions. Ion-specific multi-step microplate holders were fabricated such that each column of a 96-well microplate is spatially situated at a different location along a particle beam path. Dose, dose-averaged linear energy transfer (LETd), and dose-mean lineal energy (yd) were calculated using an experimentally validated Geant4-based Monte Carlo system. Cells were irradiated at the Heidelberg Ion Beam Therapy Center (HIT). The experimental results showed that the clonogenic survival curves of all tested ions were yd-dependent. Both helium and carbon ions achieved maximum RBEs within specific yd ranges before biological efficacy declined, indicating an overkill effect. For protons, no overkill was observed, but RBE increased distal to the Bragg peak. Measured RBE profiles strongly depend on the physical characteristics such as yd and are ion specific.
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