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Traitement du mélanome disséminé par radiothérapie interne vectorisée. Mécanismes et potentialisation.

Abstract : Melanoma is a highly aggressive skin cancer and despite the significant progress in its therapeutic management, the research keeps on developing new strategies for non-eligible patients for targeted chemotherapy or without successful therapy. The UMR990 is working on targeted radiotherapy (TRT) using ICF01012 vector labeled with iodine 131, with a high affinity for melanin and therefore for pigmented melanoma. [131I]ICF01012 induces a significant decrease of the tumoral growth in syngenic B16 models and human melanoma xenografts and a significant improvement of the survival median. The aims of the present work were i) to evaluate the dosimetry in human melanoma model, ii) to study mechanisms after TRT injection in xenografts and murin pigmented melanoma, iii) to potentiate the efficiency of this strategy using radiosensitizer. The dosimetric study showed that in SK-Mel 3 model, less pigmented than B16Bl6 tumors, the tumoral growth was significant controlled by 3 successive injections of 25 MBq. The theranostic approach is then necessary to characterize the available quantity of targets in the patient before treatment. The melanin content demonstrated that repeated injections of [131I]ICF01012 in xenografts induced an increase of melanin without any enrichment of the pheomelanin, an oxydant pigment. Interestingly, the treatment with [131I]ICF01012 reduced the number of spontaneous metastases or lung colonies in the B16Bl6 model. This treatment was then effective on small tumors or circulating cells. Consecutive mechanisms to the TRT were similar to those induced by external irradiation: DNA breaks and cell cycle arrest. However, they differed depending on p53 status of tumoral cells. The tumor regression was uncompleted after [131I]ICF01012 treatment and co-injection with radiosensitizers could improve its efficiency. We used small DNA molecules, called coDbait, mimicking the double-strand breaks to trap repairing enzymes. Syngenic model B16Bl6 and xenograft SK-Mel 3 were treated by [131I]ICF01012 and coDbait intratumoral injection. A synergistic effect of the two molecules was observed on SK-Mel 3 model, while the effect was additive in B16Bl6, a model with a fast doubling time. The coDbait destabilized the repairing process after treatment with [131I]ICF01012. Preliminary studies showed a positive effect of gadolinium nanoparticles on the efficiency of [131I] ICF01012 towards B16Bl6 tumors. The mechanisms involved remained to be defined. In conclusion, these data suggest that [131I]ICF01012 is a promising treatment for patients with pigmented metastatic melanoma.
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Claire Viallard. Traitement du mélanome disséminé par radiothérapie interne vectorisée. Mécanismes et potentialisation.. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2015. Français. ⟨NNT : 2015CLF1MM15⟩. ⟨tel-01874961⟩

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