title: Enhancement of IUdR Radiosensitization by Low-Energy Photons Results from Increased and Persistent DNA Damage.
abstract: Low-energy X-rays induce Auger cascades by photoelectric absorption in iodine present in the DNA of cells labeled with 5-iodo-2'-deoxyuridine (IUdR). This photoactivation therapy results in enhanced cellular sensitivity to radiation which reaches its maximum with 50 keV photons. Synchrotron core facilities are the only way to generate such monochromatic beams. However, these structures are not adapted for the routine treatment of patients. In this study, we generated two beams emitting photon energy means of 42 and 50 keV respectively, from a conventional 225 kV X-ray source. Viability assays performed after pre-exposure to 10 μM of IUdR for 48h suggest that complex lethal damage is generated after low energy photons irradiation compared to 137Cs irradiation (662KeV). To further decipher the molecular mechanisms leading to IUdR-mediated radiosensitization, we analyzed the content of DNA damage-induced foci in two glioblastoma cell lines and showed that the decrease in survival under these conditions was correlated with an increase in the content of DNA damage-induced foci in cell lines. Moreover, the follow-up of repair kinetics of the induced double-strand breaks showed the maximum delay in cells labeled with IUdR and exposed to X-ray irradiation. Thus, there appears to be a direct relationship between the reduction of radiation survival parameters and the production of DNA damage with impaired repair of these breaks. These results further support the clinical potential use of a halogenated pyrimidine analog combined with low-energy X-ray therapy.
authors.affiliation: INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bayart
authors.affiliation: Plateforme de Radiothérapie Expérimentale, Département de Recherche Translationnelle, Institut Curie, Orsay, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pouzoulet
authors.affiliation: Département de Radiothérapie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Calmels
authors.affiliation: Département de Radiothérapie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Dadoun
authors.affiliation: Département de Radiothérapie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Allot
authors.affiliation: CEA, DRT/LIST, Laboratoire National Henri Becquerel, Gif-sur-Yvette cedex, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Plagnard
authors.affiliation: Laboratoire des Lésions des Acides Nucléiques, Univ. Grenoble Alpes, INAC-SCIB, Grenoble, France; CEA, INAC-SCIB, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Ravanat
authors.affiliation: Département de Radiothérapie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: André
authors.initials: A
authors.lastname: Bridier
authors.affiliation: CEA, DRT/LIST, Laboratoire National Henri Becquerel, Gif-sur-Yvette cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Denozière
authors.affiliation: Department of Oncology, Radiation Oncology Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.affiliation: INSERM U1030, Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Faculté de médecine du Kremlin Bicêtre, Université Paris-Saclay, Kremlin Bicêtre, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002588:Cesium Radioisotopes; D004249:DNA Damage / Q000187:drug effects*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007065:Idoxuridine / Q000494:pharmacology*; D007700:Kinetics; D017785:Photons; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D017356:Synchrotrons; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism; D014965:X-Rays
chemical_list: D002588:Cesium Radioisotopes; D011838:Radiation-Sensitizing Agents; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D007065:Idoxuridine