Biological Effects of Passive Versus Active Scanning Proton Beams on Human Lung Epithelial Cells

Abstract

The goal was to characterize differences in cell response after exposure to active beam scanning (ABS) protons compared to a passive delivery system. Human lung epithelial (HLE) cells were evaluated at various locations along the proton depth dose profile. The dose delivered at the Bragg peak position was essentially identical (∼4 Gy) with the two techniques, but depth dose data showed that ABS resulted in lower doses at entry and more rapid drop-off after the peak. Average dose rates for the passive and ABS beams were 1.1 Gy/min and 5.1 Gy/min, respectively; instantaneous dose rates were 19.2 Gy/min and 2,300 Gy/min (to a 0.5 × 0.5 mm(2) voxel). Analysis of DNA synthesis was based on (3)H-TdR incorporation. Quantitative real-time polymerase chain reaction (RT-PCR) was done to determine expression of genes related to p53 signaling and DNA damage; a total of 152 genes were assessed. Spectral karyotyping and analyses of the Golgi apparatus and cytokines produced by the HLE cells were also performed. At or near the Bragg peak position, ABS protons resulted in a greater decrease in DNA synthesis compared to passively delivered protons. Genes with >2-fold change (P < 0.05 vs. 0 Gy) after passive proton irradiation at one or more locations within the Bragg curve were BTG2, CDKN1A, IFNB1 and SIAH1. In contrast, many more genes had >2-fold difference with ABS protons: BRCA1, BRCA2, CDC25A, CDC25C, CCNB2, CDK1, DMC1, DNMT1, E2F1, EXO1, FEN1, GADD45A, GTSE1, IL-6, JUN, KRAS, MDM4, PRC1, PTTG1, RAD51, RPA1, TNF, WT1, XRCC2, XRCC3 and XRCC6BP1. Spectral karyotyping revealed numerous differences in chromosomal abnormalities between the two delivery systems, especially at or near the Bragg peak. Percentage of cells staining for the Golgi apparatus was low after exposure to passive and active proton beams. Studies such as this are needed to ensure patient safety and make modifications in ABS delivery, if necessary.

Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation

“…Although, IL6 was not downregulated by proton radiation, it seemed like photons more strongly induce IL6 upregulation. Gridley et al previously compared transcription response to passively and actively modulated proton beams and found that IL6 was upregulated approximately twofold in a fibroblast cell line [26]. Thus, their finding also points toward IL6 being upregulated rather than downregulated by proton radiation.…”

Robust intensity‐modulated proton therapy to reduce high linear energy transfer in organs at risk

“…Currently dosimetric calculations use a constant RBE of 1.1. Although the use of a constant RBE was judged to be acceptable in passive‐scattering proton therapies, this assumption resulted from the lack of biological input parameters and oversimplified the real situation, especially for IMPT . The problem of determining RBE values is complex and involves various factors including beam radiation quality (e.g., linear energy transfer [LET]), tissue type, physical dose, and biological endpoint .…”

Hybrid 3D analytical linear energy transfer calculation algorithm based on precalculated data from Monte Carlo simulations

“…Pencil beam scanning (PBS) is a fast-developing proton delivery technique offering improved conformal dose coverage of targets and reduced dose to organs at risk (OARs) 1,2 compared to the conventional photon-based radiotherapy. However, the relative biological effectiveness (RBE) of protons is to date poorly understood [3][4][5][6][7] due to its complex dependence on several factors including the linear energy transfer (LET), biological endpoint, tissue type, physical dose, 6,8 and the uncertainty of experimental results. [9][10][11][12][13][14] As a result, it is difficult to give an accurate estimate of proton RBE for clinical dose calculations.…”