title: Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy.
abstract: Radiolabelled melanin ligands offer an interesting strategy for the treatment of disseminated pigmented melanoma. One of these molecules, ICF01012 labelled with iodine 131, induced a significant slowing of melanoma growth. Here, we have explored the combination of [131I]ICF01012 with coDbait, a DNA repair inhibitor, to overcome melanoma radioresistance and increase targeted radionuclide therapy (TRT) efficacy. In human SK-Mel 3 melanoma xenograft, the addition of coDbait had a synergistic effect on tumor growth and median survival. The anti-tumor effect was additive in murine syngeneic B16Bl6 model whereas coDbait combination with [131I]ICF01012 did not increase TRT side effects in secondary pigmented tissues (e.g. hair follicles, eyes). Our results confirm that DNA lesions induced by TRT were not enhanced with coDbait association but, the presence of micronuclei and cell cycle blockade in tumor shows that coDbait acts by interrupting or delaying DNA repair. In this study, we demonstrate for the first time, the usefulness of DNA repair traps in the context of targeted radionuclide therapy.
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.|Inserm, U 990, F-63000 Clermont-Ferrand, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Viallard
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.|Inserm, U 990, F-63000 Clermont-Ferrand, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.affiliation: Anatomopathology Department, Centre Jean Perrin, Comprehensive Cancer Center, 63011 Clermont-Ferrand, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Mishellany
authors.affiliation: Clermont Université, Université d'Auvergne, UFR Pharmacie Laboratoire de Biophysique Neurosensorielle, Inserm U 1107, F-63001 Clermont-Ferrand, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ranchon-Cole
authors.affiliation: DRCI, CHU, 63003 Clermont-Ferrand, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pereira
authors.affiliation: CNRS-UMR3347, INSERMU1021, Institut Curie, Université Paris Sud, Bat 110, Centre Universitaire 91405 Orsay, Cedex, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Herbette
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.|Inserm, U 990, F-63000 Clermont-Ferrand, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Besse
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.|Inserm, U 990, F-63000 Clermont-Ferrand, France.
authors.forename: Zied
authors.initials: Z
authors.lastname: Boudhraa
authors.affiliation: Clermont Université, Université d'Auvergne, UFR Pharmacie Laboratoire de Biophysique Neurosensorielle, Inserm U 1107, F-63001 Clermont-Ferrand, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacquemot
authors.affiliation: Anatomopathology Department, Centre Jean Perrin, Comprehensive Cancer Center, 63011 Clermont-Ferrand, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Cayre
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.|Inserm, U 990, F-63000 Clermont-Ferrand, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Miot-Noirault
authors.affiliation: DNA Therapeutics, SA, 91058 Evry Cedex, France.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Sun
authors.affiliation: CNRS-UMR3347, INSERMU1021, Institut Curie, Université Paris Sud, Bat 110, Centre Universitaire 91405 Orsay, Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
authors.affiliation: Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.|Inserm, U 990, F-63000 Clermont-Ferrand, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Degoul
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004247:DNA / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011810:Quinoxalines / Q000494:pharmacology; D000090324:Tumor Protein, Translationally-Controlled 1; D023041:Xenograft Model Antitumor Assays
chemical_list: D007457:Iodine Radioisotopes; C530303:N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide; D011810:Quinoxalines; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D004247:DNA
keywords: DNA repair; coDbait; melanoma; targeted radionuclide therapy