Research Papers:
Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy
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Abstract
Claire Viallard1,2, Jean-Michel Chezal1,2, Florence Mishellany3, Isabelle Ranchon-Cole4, Bruno Pereira5, Aurélie Herbette6, Sophie Besse1,2, Zied Boudhraa1,2, Nathalie Jacquemot4, Anne Cayre3, Elisabeth Miot-Noirault1,2, Jian-Sheng Sun7, Marie Dutreix6, Françoise Degoul1,2
1Clermont Université, Université d’Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France
2Inserm, U 990, F-63000 Clermont-Ferrand, France
3Anatomopathology Department, Centre Jean Perrin, Comprehensive Cancer Center, 63011 Clermont-Ferrand, France
4Clermont Université, Université d’Auvergne, UFR Pharmacie Laboratoire de Biophysique Neurosensorielle, Inserm U 1107, F-63001 Clermont-Ferrand, France
5DRCI, CHU, 63003 Clermont-Ferrand, France
6CNRS-UMR3347, INSERMU1021, Institut Curie, Université Paris Sud, Bat 110, Centre Universitaire 91405 Orsay, Cedex, France
7DNA Therapeutics, SA, 91058 Evry Cedex, France
Correspondence to:
Françoise Degoul, e-mail: [email protected]
Keywords: targeted radionuclide therapy, melanoma, coDbait, DNA repair
Received: October 16, 2015 Accepted: January 24, 2016 Published: February 12, 2016
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.
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PII: 7340