Promising pre-clinical validation of targeted radionuclide therapy using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment

Targeted internal radionuclide therapy (TRT) would be an effective alternative to current therapies for dissemi- nated melanoma treatment. At our institution, a class of iodobenzamides has been developed as potent melanoma- seeking agents. This review described the preclinical vali- dations of a quinoxaline derivative molecule (ICF01012) as tracer for TRT application. It was selected for its high, specific and long-lasting uptake in tumour with rapid clear- ance from non-target organs providing suitable dosimetry parameters for TRT. Extended in vivo study of metabolic profiles confirmed durable tumoural concentration of the unchanged molecule form. Moreover melanin specificity of ICF01012 was determined by binding assay with syn- thetic melanin and in vivo by SIMS imaging. Then, we showed in vivo that [131I] ICF01012 treatment drastically inhibited growth of B16F0, B16Bl6 and M4Beu tumours whereas [131I] NaI or unlabelled ICF01012 treatment was without significant effect. Histological analysis showed that residual tumour cells exhibit a significant loss of aggres- siveness after treatment. This anti-tumoural effect was associated with a lengthening of the treated-mice survival time and an inhibition of lung dissemination for B16Bl6 model. Results presented here support the concept of TRT using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment.<br /

Expression and function of neurotrophins and their receptors in human melanocytes.

Melanocytes and cells of the nervous system are of common ectodermal origin and neurotrophins (NT) have been shown to be released by human keratinocytes. We investigated the expression and function of NT [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, NT-4/-5] and their receptors in human melanocytes. Human melanocytes produce all NT in different amounts, whereas they only release NT-4. NT-4 release is downregulated, whereas NT-3 is upregulated by ultraviolet (UVB) irradiation. Melanocytes treated with phorbol 12-myristate 13-acetate (PMA) express TrkA and TrkB, but not TrkC. NT fail to stimulate melanocyte proliferation, whereas they stimulate the synthesis of tyrosinase and tyrosinase-related protein-1 (TRP-1). Finally, NT-3, NT-4 and NGF increase melanin production. Taken together, these results demonstrate an intriguing interaction between melanocytes and the nervous system. We speculate that NT could be considered the target of therapy for disorders of skin pigmentation

Nouveaux traceurs TEMP : exemple des traceurs des protéoglycanes et de la mélanine

International audienceThe majority of research program on new radiopharmaceutics turn to tracers used for positron emission tomography (PET). Only a few teamswork on new non fluorine labeled tracers. However, the coming of SPECT/CT gamma cameras, the arrival of semi-conductors gamma camerasshould boost the development of non-PET tracers.We exhibit in this article the experience acquired by our laboratory in the conception and designof two new non fluorine labelled compounds. The 99mTc-NTP 15-5 which binds to proteoglycans could be used for the diagnosis and staging ofosteoarthritis and chondrosarcoma. The iodobenzamides, specific to the melanin, are nowadays compared to 18F-fluorodeoxyglucose in a phase IIIclinical trial for the diagnosis and detection of melanoma metastasis. Our last development focus on BZA heteroaromatic analogues usable formelanoma treatment.La plupart des programmes de recherche sur les nouveaux radiopharmaceutiques portent actuellement sur les traceurs utilisés en tomographie par émission de positons (TEP). Seules quelques équipes continuent à travailler sur des nouveaux traceurs non fluorés. Toutefois, l'arrivée des gammas caméras TEMP/TDM et le frémissement des caméras à semi-conducteur, pourraient donner un nouvel élan au développement des traceurs non TEP. Nous exposons dans cet article l'expérience acquise par notre laboratoire dans la conception et l'étude de deux nouvelles familles de molécules non fluorées. Le 99m Tc-NTP 15-5 se lie sur les protéoglycanes et pourrait ainsi être utilisé pour le diagnostic ou suivi de l'arthrose et du chondrosarcome. Les iodobenzamides, traceurs de la mélanine, sont actuellement comparés au 18 F-fluorodéoxyglucose dans un essai de phase III pour le suivi et le diagnostic de métastases de mélanome. Nos derniers travaux portent sur de nouveaux analogues hétérocycliques utilisables pour le traitement du mélanome