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: Claire Viallard, Jean-Michel Chezal, Florence Mishellany, Isabelle Ranchon-Cole, Bruno Pereira, Aurélie Herbette, Sophie Besse, Zied Boudhraa, Nathalie Jacquemot, Anne Cayre, Elisabeth Miot-Noirault, Jian-Sheng Sun, Marie Dutreix, Françoise Degoul
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 11 Pg. 12927-36 (Mar 15 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26887045 (Publication Type: Journal Article)

Chemical References

• Iodine Radioisotopes
• N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide
• Quinoxalines
• Tpt1 protein, mouse
• Tumor Protein, Translationally-Controlled 1
• DNA

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• DNA (pharmacology)
• DNA Repair (drug effects)
• Drug Synergism
• Female
• Humans
• Iodine Radioisotopes (pharmacology)
• Male
• Melanoma (pathology)
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Quinoxalines (pharmacology)
• Tumor Protein, Translationally-Controlled 1
• Xenograft Model Antitumor Assays