Low-LET Proton Irradiation of A549 Non-small Cell Lung Adenocarcinoma Cells: Dose Response and RBE Determination

Abstract

Since 1957, broad proton beam radiotherapy with a spread out Bragg peak has been used for cancer treatment. More recently, studies on the use of proton therapy in the treatment of non-small cell lung cancer (NSCLC) were performed and although the benefit of using protons for the treatment of NSCLC is recognized, more work is needed to gather additional data for the understanding of cell response. Human A549 cell survival was evaluated by colony forming assay 11 days after 10 keV/μm proton beam irradiation at 0.1 and 1 Gy/min. The residual energy of the proton beam at the location of the irradiated cells was 3.9 MeV. In parallel, early effects on the cell viability and DNA damage were assessed and DNA synthesis was measured. The survival curve obtained was fitted with both the linear and the induced-repair models, as a hyper-radiosensitivity was evidenced at very low doses. Above 0.5 Gy, a linear shape was observed with the α parameter equal to 0.824 ± 0.029 Gy(-1). In addition, early cell death and cell proliferation arrest were enhanced. Moreover, a clear correlation between DNA damage and surviving fraction was observed. Finally, comparisons with X ray results indicate that proton irradiation at 10 keV/μm enhanced the tumor radiosensitivity with a significant dose-dependent decrease in the survival fraction. The RBE value of 1.9 ± 0.4 obtained for a 10% survival support this observation.

Determining if low dose hyper-radiosensitivity (HRS) can be exploited to provide a therapeutic advantage: A cell line study in four glioblastoma multiforme (GBM) cell lines

“…The existence of HRS after acute low-dose X-ray exposures is now irrefutable. More recently, cell line studies have also demonstrated HRS after high linear energy transfer (LET) exposures (Tsoulou et al 2001, Xue et al 2009, Petrovic et al 2010, Wera et al 2013, supporting earlier reports using single doses of pi-mesons or neutrons (Marples et al 1994, Marples andSkov 1996).…”

Optimizing radiotherapy protocols using computer automata to model tumour cell death as a function of oxygen diffusion processes

“…1 illustrates the flow chart for implementing mitotic catastrophe. This simple mechanism is in good agreement with the general consensus of how mitotic catastrophe occurs 35 and it circumvents the need to introduce another parameter required for the cell death delay model that we and others have previously used 6, 33 . It also neglects senescence and apoptosis as other mechanisms for radiation-induced tumour cell death.…”

“…Death and cell clearing is not instantaneous after exposure and tumours undergoing radiotherapy do not shrink at the rate one would expect from measured in vitro cell death. Recent clonogenic survival data on lung cancer cells have in fact shown that it can take as long as 14 days post-exposure before a cell actually disappears 33 . Similarly, we have shown using time lapse imaging of normal human breast cells in vitro 34 that cell death is asynchronous following exposure to the same dose of x-rays with large variations between cells.…”

New challenges in high-energy particle radiobiology

“…47 A recent experiment in a human NSCLC cell line reported an RBE 5 1.9 for 3.9 MeV protons compared with X-rays. 48 The Tsukuba proton beam line used for the NSCLC treatment 42 has been used for in vitro experiments in different human cell lines. 49 Apoptosis induction was greater than two-fold the level induced by 10 MeV X-ray.…”