Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation

Fontana, A.; Augsburger, Marc A.; Grosse, Nicole; Gückenberger, Matthias; Lomax, Anthony; Sartori, Alessandro A.; Pruschy, Martin

doi:10.1016/j.radonc.2015.08.014

Cited by 105 publications

(114 citation statements)

References 18 publications

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“…For example, homologous recombination is required for the repair of DSBs in late S- and G2-phases of the cell cycle. It has been shown that defective homologous recombination increases the RBE for cell survival [44, 68, 70–72]. There are research efforts toward identifying biomarkers to identify patients with RBE values either low or high compared with the overall patient population [44, 68, 70].…”

Section: Rbe Variations In Patientsmentioning

confidence: 99%

Proton Relative Biological Effectiveness – Uncertainties and Opportunities

Paganetti

2018

International Journal of Particle Therapy

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Proton therapy treatments are prescribed using a biological effectiveness relative to photon therapy of 1.1, that is, proton beams are considered to be 10% more biologically effective. Debate is ongoing as to whether this practice needs to be revised. This short review summarizes current knowledge on relative biological effectiveness variations and uncertainties in vitro and in vivo. Clinical relevance is discussed and strategies toward biologically guided treatment planning are presented.

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Section: Rbe Variations In Patientsmentioning

confidence: 99%

Proton Relative Biological Effectiveness – Uncertainties and Opportunities

Paganetti

2018

International Journal of Particle Therapy

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“…However, the increased resistance to protons is less pronounced than the increased resistance to x-rays. The results indicate that DNA damage induced by protons is less amenable to DNA-PKcs–dependent repair than damage induced by x-rays, a result that is not inconsistent with studies showing that homologous recombination-defective cells (NHEJ competent) exhibited an increased proton RBE [24, 25]. …”

Section: Discussionmentioning

confidence: 68%

“…A review of the literature suggests a trend for a higher proton RBE in x-ray–resistant versus x-ray–sensitive cells [20–23]. However, in studies using wild-type and DNA-PKcs–deficient or DNA-PKcs–inhibited cells (or other key constituents of NHEJ), a significant proton RBE difference between sensitive and resistant cells has generally not been observed [15, 16, 24, 25]. …”

Section: Introductionmentioning

confidence: 99%

The Relative Biological Effect of Spread-Out Bragg Peak Protons in Sensitive and Resistant Tumor Cells

Lin

Chen

et al. 2017

International Journal of Particle Therapy

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Purpose Variations in the radiosensitivity of tumor cells within and between tumors impact tumor response to radiation, including the dose required to achieve permanent local tumor control. The increased expression of DNA-PKcs, a key component of a major DNA damage repair pathway in tumors treated by radiation, suggests that DNA-PKcs–dependent repair is likely a cause of tumor cell radioresistance. This study evaluates the relative biological effect of spread-out Bragg-peak protons in DNA-PKcs–deficient cells and the same cells transfected with a functional DNA-PKcs gene. Materials and Methods A cloned radiation-sensitive DNA-PKcs–deficient tumor line and its DNA-PKcs–transfected resistant counterpart were used in this study. The presence of functional DNA-PKcs was evaluated by DNA-PKcs autophosphorylation. Cells to be proton irradiated or x-irradiated were obtained from the same single cell suspension and dilution series to maximize precision. Cells were concurrently exposed to 6-MV x-rays or mid 137-MeV spread-out Bragg peak protons and cultured for colony formation. Results The surviving fraction data were well fit by the linear-quadratic model for each of 8 survival curves. The results suggest that the relative biological effectiveness of mid spread-out Bragg peak protons is approximately 6% higher in DNA-PKcs–mediated resistant tumor cells than in their DNA-PKcs–deficient and radiation-sensitive counterpart. Conclusion DNA-PKcs–dependent repair of radiation damage is less capable of repairing mid spread-out Bragg peak proton lesions than photon-induced lesions, suggesting protons may be more efficient at sterilizing DNA-PKcs–expressing cells that are enriched in tumors treated by conventional fractionated dose x-irradiation.

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“…This difference is due to a difference in the complexity of DNA damage induced by these two radiation types. A higher level of clustered DNA damage lesions and locally multiply damaged sites (LMDS) has been previously reported after proton irradiation [15]. Observed differences might also be due a difference in cell death pathways [16].…”

Section: Resultsmentioning

confidence: 75%

Effects of 60 MeV Protons and 250 kV X-Rays on Cell Viability

et al. 2016

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Particle radiotherapy such as the one using proton beams, provides a successful treatment approach in many cancer types. However, the cellular and molecular mechanisms by which proton irradiation induces cell death, particularly in a human peripheral blood lymphocyte model has not been examined in detail. Comparative studies of the biological effects, such as cell death, of particle therapy versus conventional X-rays treatment are of utmost importance. Here, we compared the viability of human peripheral blood lymphocyte following in vitro irradiation with protons (therapeutic 60 MeV proton beam) and photon beam (250 kV, X-rays), by applying separate doses within the range of 0.3-4.0 Gy. Cell viability was assessed 1 and 4 h after irradiation with protons and X-rays by the FITC-Annexin V labelling procedure (Apoptotic & Necrotic & Healthy Cells Quantification Kit, Biotium). Results showed that irradiation with both radiation types reduced the number of viable cells in a dose-dependent manner, as assessed as a function of the duration of post-irradiation time. Protons proved more fatal to the cells treated than X-ray photons. This demonstrates a difference in cell viability after irradiation with protons and photons in a human peripheral blood lymphocyte model.

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Differential DNA repair pathway choice in cancer cells after proton- and photon-irradiation

Abstract: A differential DNA damage response with enhanced susceptibility of HR-deficient tumor cells to proton-irradiation and increased sensitivity of photon-irradiated tumor cells to NHEJ inhibitors were demonstrated.

Cited by 105 publications

References 18 publications

Proton Relative Biological Effectiveness – Uncertainties and Opportunities

Proton Relative Biological Effectiveness – Uncertainties and Opportunities

The Relative Biological Effect of Spread-Out Bragg Peak Protons in Sensitive and Resistant Tumor Cells

Effects of 60 MeV Protons and 250 kV X-Rays on Cell Viability

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