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Title: Involvement of the Artemis Protein in the Relative Biological Efficiency Observed With the 76-MeV Proton Beam Used at the Institut Curie Proton Therapy Center in Orsay

Abstract

Purpose: Previously we showed that the relative biological efficiency for induced cell killing by the 76-MeV beam used at the Institut Curie Proton Therapy Center in Orsay increased with depth throughout the spread-out Bragg peak (SOBP). To investigate the repair pathways underlying this increase, we used an isogenic human cell model in which individual DNA repair proteins have been depleted, and techniques dedicated to precise measurements of radiation-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). Methods and Materials: The 3-Gy surviving fractions of HeLa cells individually depleted of Ogg1, XRCC1, and PARP1 (the base excision repair/SSB repair pathway) or of ATM, DNA-PKcs, XRCC4, and Artemis (nonhomologous end-joining pathway) were determined at the 3 positions previously defined in the SOBP. Quantification of incident SSBs and DSBs by the alkaline elution technique and 3-dimensional (3D) immunofluorescence of γ-H2AX foci, respectively, was performed in SQ20 B cells. Results: We showed that the amount of SSBs and DSBs depends directly on the particle fluence and that the increase in relative biological efficiency observed in the distal part of the SOBP is due to a subset of lesions generated under these conditions, leading to cell death via a pathway in which the Artemis protein plays a centralmore » role. Conclusions: Because therapies like proton or carbon beams are now being used to treat cancer, it is even more important to dissect the mechanisms implicated in the repair of the lesions generated by these particles. Additionally, alteration of the expression or activity of the Artemis protein could be a novel therapeutic tool before high linear energy transfer irradiation treatment.« less

Authors:
 [1];  [2];  [2];  [1];  [3];  [4];  [1]; ;  [3];  [2];  [3];  [2]
  1. Institut Curie Centre de Protonthérapie d'Orsay, Centre Universitaire, Orsay (France)
  2. (France)
  3. Institut Curie, Centre Universitaire, Orsay (France)
  4. Centre d'Etude Atomique, Direction des Sciences du Vivant, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etude des Prions et des Infections Atypiques, Fontenay-aux-Roses (France)
Publication Date:
OSTI Identifier:
22420406
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 90; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; 62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; BIOLOGICAL PATHWAYS; BRAGG CURVE; CELL KILLING; DNA; EFFICIENCY; EXCISION REPAIR; HELA CELLS; ION BEAMS; LET; MATERIALS; MEV RANGE 10-100; NEOPLASMS; PROTON BEAMS; RADIOTHERAPY; STRAND BREAKS; THREE-DIMENSIONAL CALCULATIONS

Citation Formats

Calugaru, Valentin, Institut Curie, Centre Universitaire, Orsay, INSERM U612, Centre Universitaire, Orsay, Nauraye, Catherine, Cordelières, Fabrice P., Biard, Denis, De Marzi, Ludovic, Hall, Janet, Favaudon, Vincent, INSERM U612, Centre Universitaire, Orsay, Mégnin-Chanet, Frédérique, E-mail: frederique.megnin@inserm.fr, and INSERM U612, Centre Universitaire, Orsay. Involvement of the Artemis Protein in the Relative Biological Efficiency Observed With the 76-MeV Proton Beam Used at the Institut Curie Proton Therapy Center in Orsay. United States: N. p., 2014. Web. doi:10.1016/J.IJROBP.2014.05.018.
Calugaru, Valentin, Institut Curie, Centre Universitaire, Orsay, INSERM U612, Centre Universitaire, Orsay, Nauraye, Catherine, Cordelières, Fabrice P., Biard, Denis, De Marzi, Ludovic, Hall, Janet, Favaudon, Vincent, INSERM U612, Centre Universitaire, Orsay, Mégnin-Chanet, Frédérique, E-mail: frederique.megnin@inserm.fr, & INSERM U612, Centre Universitaire, Orsay. Involvement of the Artemis Protein in the Relative Biological Efficiency Observed With the 76-MeV Proton Beam Used at the Institut Curie Proton Therapy Center in Orsay. United States. doi:10.1016/J.IJROBP.2014.05.018.
Calugaru, Valentin, Institut Curie, Centre Universitaire, Orsay, INSERM U612, Centre Universitaire, Orsay, Nauraye, Catherine, Cordelières, Fabrice P., Biard, Denis, De Marzi, Ludovic, Hall, Janet, Favaudon, Vincent, INSERM U612, Centre Universitaire, Orsay, Mégnin-Chanet, Frédérique, E-mail: frederique.megnin@inserm.fr, and INSERM U612, Centre Universitaire, Orsay. Mon . "Involvement of the Artemis Protein in the Relative Biological Efficiency Observed With the 76-MeV Proton Beam Used at the Institut Curie Proton Therapy Center in Orsay". United States. doi:10.1016/J.IJROBP.2014.05.018.
@article{osti_22420406,
title = {Involvement of the Artemis Protein in the Relative Biological Efficiency Observed With the 76-MeV Proton Beam Used at the Institut Curie Proton Therapy Center in Orsay},
author = {Calugaru, Valentin and Institut Curie, Centre Universitaire, Orsay and INSERM U612, Centre Universitaire, Orsay and Nauraye, Catherine and Cordelières, Fabrice P. and Biard, Denis and De Marzi, Ludovic and Hall, Janet and Favaudon, Vincent and INSERM U612, Centre Universitaire, Orsay and Mégnin-Chanet, Frédérique, E-mail: frederique.megnin@inserm.fr and INSERM U612, Centre Universitaire, Orsay},
abstractNote = {Purpose: Previously we showed that the relative biological efficiency for induced cell killing by the 76-MeV beam used at the Institut Curie Proton Therapy Center in Orsay increased with depth throughout the spread-out Bragg peak (SOBP). To investigate the repair pathways underlying this increase, we used an isogenic human cell model in which individual DNA repair proteins have been depleted, and techniques dedicated to precise measurements of radiation-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). Methods and Materials: The 3-Gy surviving fractions of HeLa cells individually depleted of Ogg1, XRCC1, and PARP1 (the base excision repair/SSB repair pathway) or of ATM, DNA-PKcs, XRCC4, and Artemis (nonhomologous end-joining pathway) were determined at the 3 positions previously defined in the SOBP. Quantification of incident SSBs and DSBs by the alkaline elution technique and 3-dimensional (3D) immunofluorescence of γ-H2AX foci, respectively, was performed in SQ20 B cells. Results: We showed that the amount of SSBs and DSBs depends directly on the particle fluence and that the increase in relative biological efficiency observed in the distal part of the SOBP is due to a subset of lesions generated under these conditions, leading to cell death via a pathway in which the Artemis protein plays a central role. Conclusions: Because therapies like proton or carbon beams are now being used to treat cancer, it is even more important to dissect the mechanisms implicated in the repair of the lesions generated by these particles. Additionally, alteration of the expression or activity of the Artemis protein could be a novel therapeutic tool before high linear energy transfer irradiation treatment.},
doi = {10.1016/J.IJROBP.2014.05.018},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 90,
place = {United States},
year = {Mon Sep 01 00:00:00 EDT 2014},
month = {Mon Sep 01 00:00:00 EDT 2014}
}
  • Purpose: Treatment planning in proton therapy uses a generic value for the relative biological efficiency (RBE) of 1.1 throughout the spread-out Bragg peak (SOBP) generated. In this article, we report on the variation of the RBE with depth in the SOBP of the 76- and 201-MeV proton beams used for treatment at the Institut Curie Proton Therapy Center in Orsay. Methods and Materials: The RBE (relative to {sup 137}Cs {gamma}-rays) of the two modulated proton beams at three positions in the SOBP was determined in two human tumor cells using as endpoints clonogenic cell survival and the incidence of DNAmore » double-strand breaks (DSBs) as measured by pulse-field gel electrophoresis without and with enzymatic treatment to reveal clustered lesions. Results: The RBE for induced cell killing by the 76-MeV beam increased with depth in the SOBP. However for the 201-MeV protons, it was close to that for {sup 137}Cs {gamma}-rays and did not vary significantly. The incidence of DSBs and clustered lesions was higher for protons than for {sup 137}Cs {gamma}-rays, but did not depend on the proton energy or the position in the SOBP. Conclusions: Until now, little attention has been paid to the variation of RBE with depth in the SOBP as a function of the nominal energy of the primary proton beam and the molecular nature of the DNA damage. The RBE increase in the 76-MeV SOBP implies that the tumor tissues at the distal end receives a higher biologically equivalent dose than at the proximal end, despite a homogeneous physical dose. This is not the case for the 201-MeV energy beam. The precise determination of the effects of incident beam energy, modulation, and depth in tissues on the linear energy transfer-RBE relationship is essential for treatment planning.« less
  • Purpose: This study reports the results of proton beam radiotherapy based on a retrospective series of patients treated for uveal melanoma at the Orsay Center. Methods and Materials: Between September 1991 and September 2001, 1,406 patients with uveal melanoma were treated by proton beam radiotherapy. A total dose of 60 cobalt Gray equivalent (CGE) was delivered in 4 fractions on 4 days. Survival rates were determined using Kaplan-Meier estimates. Prognostic factors were determined by multivariate analysis using the Cox model. Results: The median follow-up was 73 months (range, 24-142 months). The 5-year overall survival and metastasis-free survival rates were 79%more » and 80.6%, respectively. The 5-year local control rate was 96%. The 5-year enucleation for complications rate was 7.7%. Independent prognostic factors for overall survival were age (p < 0.0001), gender (p < 0.0003), tumor site (p < 0.0001), tumor thickness (p = 0.02), tumor diameter (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.003). Independent prognostic factors for metastasis-free survival were age (p = 0.0042), retinal detachment (p = 0.01), tumor site (p < 0.0001), tumor volume (p < 0.0001), local recurrence (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.002). Independent prognostic factors for local control were tumor diameter (p = 0.003) and macular area receiving at least 30 CGE (p = 0.01). Independent prognostic factors for enucleation for complications were tumor thickness (p < 0.0001) and lens volume receiving at least 30 CGE (p = 0.0002). Conclusion: This retrospective study confirms that proton beam radiotherapy ensures an excellent local control rate. Further clinical studies are required to decrease the incidence of postirradiation ocular complications.« less
  • Purpose: For prostate treatments, robust evidence regarding the superiority of either intensity modulated radiation therapy (IMRT) or proton therapy is currently lacking. In this study we investigated the circumstances under which proton therapy should be expected to outperform IMRT, particularly the proton beam orientations and relative biological effectiveness (RBE) assumptions. Methods and Materials: For 8 patients, 4 treatment planning strategies were considered: (A) IMRT; (B) passively scattered standard bilateral (SB) proton beams; (C) passively scattered anterior oblique (AO) proton beams, and (D) AO intensity modulated proton therapy (IMPT). For modalities (B)-(D) the dose and linear energy transfer (LET) distributions weremore » simulated using the TOPAS Monte Carlo platform and RBE was calculated according to 3 different models. Results: Assuming a fixed RBE of 1.1, our implementation of IMRT outperformed SB proton therapy across most normal tissue metrics. For the scattered AO proton plans, application of the variable RBE models resulted in substantial hotspots in rectal RBE weighted dose. For AO IMPT, it was typically not possible to find a plan that simultaneously met the tumor and rectal constraints for both fixed and variable RBE models. Conclusion: If either a fixed RBE of 1.1 or a variable RBE model could be validated in vivo, then it would always be possible to use AO IMPT to dose-boost the prostate and improve normal tissue sparing relative to IMRT. For a cohort without rectum spacer gels, this study (1) underlines the importance of resolving the question of proton RBE within the framework of an IMRT versus proton debate for the prostate and (2) highlights that without further LET/RBE model validation, great care must be taken if AO proton fields are to be considered for prostate treatments.« less
  • The clinical use of protons for the treatment of cancer is one of the most technologically advanced forms of therapy. The newly commissioned M.D. Anderson Cancer Center, Proton Therapy Center Houston is one of the newest facilities offering a complete range of advanced proton therapies designed specifically to minimize treatment-related normal tissue toxicity. As an integral part of the clinical commissioning of this proton beam, we performed an in vivo assessment of the relative biologic effectiveness of the 250-MeV protons relative to standard cobalt {sup 60} using the jejunal crypt microcolony assay in mice. Our data are consistent with amore » generic relative biologic effectiveness of 1.1, and this relative biologic effectiveness is in agreement with that used to describe most other clinical proton therapy beams worldwide.« less