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Oncotarget. 2016 Mar 15;7(11):12927-36. doi: 10.18632/oncotarget.7340.

Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy.

Author information

1
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.
2
Inserm, U 990, F-63000 Clermont-Ferrand, France.
3
Anatomopathology Department, Centre Jean Perrin, Comprehensive Cancer Center, 63011 Clermont-Ferrand, France.
4
Clermont Université, Université d'Auvergne, UFR Pharmacie Laboratoire de Biophysique Neurosensorielle, Inserm U 1107, F-63001 Clermont-Ferrand, France.
5
DRCI, CHU, 63003 Clermont-Ferrand, France.
6
CNRS-UMR3347, INSERMU1021, Institut Curie, Université Paris Sud, Bat 110, Centre Universitaire 91405 Orsay, Cedex, France.
7
DNA Therapeutics, SA, 91058 Evry Cedex, France.

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.

KEYWORDS:

DNA repair; coDbait; melanoma; targeted radionuclide therapy

PMID:
26887045
PMCID:
PMC4914332
DOI:
10.18632/oncotarget.7340
[Indexed for MEDLINE]
Free PMC Article

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