title: In vivo efficacy of melanoma internal radionuclide therapy with a 131I-labelled melanin-targeting heteroarylcarboxamide molecule.
abstract: The development of alternative therapies for melanoma treatment is of great interest as long-term tumour regression is not achieved with new targeted chemotherapies on selected patients. We previously demonstrated that radioiodinated heteroarylcarboxamide ([131I]ICF01012) induced a strong anti-tumoural effect by inhibiting both primary tumour growth and dissemination process in a B16BL6 melanoma model. In our study, we show that a single injection of [131I]ICF01012 (ranging from 14.8 to 22.2 MBq) was effective and associated with low and transient haematological toxicity. Concerning pigmented organs, cutaneous melanocytes and skin were undamaged. In 30% of treated animals, no histological alteration of retina was observed, and in the remaining 70%, damages were restricted to the optic nerve area. Using the Medical Internal Radiation Dose methodology, we determined that the absorbed dose in major organs is very low (<4 Gy) and that a delivery of 30 Gy to the tumour is sufficient for an effective anti-tumoural response. Molecular analyses of treated tumours showed a strong radiobiological effect with a decrease in proliferation, survival and pro-angiogenic-related markers and an increase in tumour suppressor gene expression, melanogenesis and anti-angiogenic markers. All these features are in accordance with a tumour cell death mechanism that mainly occurs by mitotic catastrophe and provide a better understanding of in vivo anti-tumoural effects of [131I] radionuclide. Our findings raise [131I]ICF01012 a good candidate for disseminated melanoma treatment and strongly support transfer of [131I]ICF01012 to clinical trial.
authors: Imagerie Moléculaire et Thérapie Vectorisée, Université d'Auvergne, Clermont Université, Clermont-Ferrand, France.
authors: Françoise
authors: F
authors: Degoul
authors: Michèle
authors: M
authors: Borel
authors: Nathalie
authors: N
authors: Jacquemot
authors: Sophie
authors: S
authors: Besse
authors: Yves
authors: Y
authors: Communal
authors: Florence
authors: F
authors: Mishellany
authors: Janine
authors: J
authors: Papon
authors: Frédérique
authors: F
authors: Penault-Llorca
authors: Denise
authors: D
authors: Donnarieix
authors: Michel
authors: M
authors: Doly
authors: Lydia
authors: L
authors: Maigne
authors: Elisabeth
authors: E
authors: Miot-Noirault
authors: Anne
authors: A
authors: Cayre
authors: Jacques
authors: J
authors: Cluzel
authors: Nicole
authors: N
authors: Moins
authors: Jean-Michel
authors: JM
authors: Chezal
authors: Mathilde
authors: M
authors: Bonnet
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000528:radiation effects; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008297:Male; D008543:Melanins / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011810:Quinoxalines / Q000627:therapeutic use*
chemical_list: D007457:Iodine Radioisotopes; D008543:Melanins; C530303:N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide; D011810:Quinoxalines
keywords: melanin; melanoma; mitotic catastrophe cell death; radiotherapy