n-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide and Melanoma

Dosimetry for melanoma-targeted radionuclide therapy (TRT) with [. Ex vivo biodistribution (i.v. injection: 370 kBq/kg, n = 2 per point) is performed on blood, eyes, brain, lung, liver, kidneys, heart, stomach, and spleen. Dosimetry calculations follow the MIRD formalism: S values are calculated from CT images using the GATE Monte Carlo platform and activity distributions are obtained from SPECT-CT imaging (i.v. injection: 37 MBq/kg n = 3 per point). A specific study is presented to assess dose to human retina.. This study sustains [

Topics: Animals; Female; Humans; Iodine Radioisotopes; Male; Melanoma; Quinoxalines; Rabbits; Radiometry; Radiotherapy Dosage; Single Photon Emission Computed Tomography Computed Tomography; Software; Tissue Distribution; Tumor Protein, Translationally-Controlled 1

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; DNA; DNA Repair; Drug Synergism; Female; Humans; Iodine Radioisotopes; Male; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; Quinoxalines; Tumor Protein, Translationally-Controlled 1; Xenograft Model Antitumor Assays

In the search for more selective anticancer drugs, we designed and synthesized seven conjugates varying the structure of the linker connecting the 5-iodo-2'-deoxyuridine (IUdR) to the ICF 01012 melanoma-carrier for potential intratumoural specific drug release. Chemical and in vitro metabolic stability evaluations showed that, except for the ester conjugate (1), the ketal (2b), acetal (2a), carbonate (4) and carbamate (3) conjugates were compatible with our approach. The acetal (2a) and its PEGylated derivative (2c) were of particular interest for further in vivo development owing to their respective pH-dependent stability and limited metabolic degradation in order to exploit the acidic subcellular environment of malignant melanocytes to trigger the release of therapeutics upon internalization in cells.

Topics: Acetals; Antineoplastic Agents; Cells, Cultured; Drug Delivery Systems; Drug Stability; Humans; Idoxuridine; Melanoma; Molecular Structure; Quinoxalines

Targeted internal radionuclide therapy (TRT) could be an efficient, specific way to treat disseminated melanoma. Based on a previous pharmacomodulation study, we selected a quinoxaline-derived molecule (ICF01012) for its melanin specificity and kinetic properties suitable for TRT. Here, we determined the efficacy of [(131)I]ICF01012 radiotherapy in vitro and in vivo in relation to melanogenesis using human melanoma models. [(125)I]ICF01012 uptake was first assessed in relation to melanin content. We found that melanin distribution in different models was representative of pathology seen in human tumours: melanin content was high in the extracellular space of SKMel3 tumours, and accumulated primarily in melanophages in M4Beu tumours. Targeted [(131)I]ICF01012 radiotherapy had a strong anti-tumoural efficacy in pigmented versus unpigmented tumours, regardless of target distribution and content. This study supports the use of melanin targeting with (131)I-labelled iodoquinoxaline for effective treatment of melanoma.

Topics: Animals; Cell Line, Tumor; Humans; Iodine Radioisotopes; Male; Melanins; Melanoma; Melanosomes; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Transplantation; Pigmentation; Quinoxalines; Skin Neoplasms; Transplantation, Heterologous; Tumor Protein, Translationally-Controlled 1