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Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter

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Summary

The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodobenzamides or analogs are known to possess specific affinity for melanoma tissue. New heteroaromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using 125I, which emits Auger electrons and gives high-energy, localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with 125I, the two compounds induced in vitro a significant radiotoxicity to B16F0 melanoma cells. Nevertheless, the acridine compound appeared more radiotoxic than the acridone compound. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with acridone derivative, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. In conclusion, the acridine derivative with a higher nuclear localization appeared a better candidate for application in targeted radionuclide therapy using 125I.

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Acknowledgements

We thank: Danièle CARREZ, Ing., U 759 Inserm/Curie, Orsay, for her technical support. The authors are grateful to the Inserm and the Région Auvergne for awarding Maryline Gardette research grants, and the French “Agence Nationale de la Recherche” and the “Ligue Régionale contre le Cancer” for their financial support.

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Authors and Affiliations

  1. Inserm UMR 990, BP 184, Clermont-Ferrand, cedex 63005, France

    Maryline Gardette, Janine Papon, Mathilde Bonnet, Pierre Labarre, Elisabeth Miot-Noirault, Jean-Claude Madelmont, Jean-Michel Chezal & Nicole Moins

  2. Clermont Université, Université d’Auvergne, UMR 990, BP 10448, 63000, Clermont-Ferrand, France

    Maryline Gardette, Janine Papon, Mathilde Bonnet, Pierre Labarre, Elisabeth Miot-Noirault, Jean-Claude Madelmont, Jean-Michel Chezal & Nicole Moins

  3. Centre Jean Perrin, Clermont-Ferrand, 63011, France

    Maryline Gardette, Janine Papon, Mathilde Bonnet, Pierre Labarre, Elisabeth Miot-Noirault, Jean-Claude Madelmont, Jean-Michel Chezal & Nicole Moins

  4. Université de Bourgogne, EA 3660, BP 89700, 21079, Dijon, France

    Nicolas Desbois

  5. Laboratoire de Microscopie Ionique, Institut Curie, Orsay, 91405, France

    Ting-Dee Wu & Jean-Luc Guerquin-Kern

  6. Inserm U 759, Orsay, 91405, France

    Ting-Dee Wu & Jean-Luc Guerquin-Kern

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  1. Maryline Gardette
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  2. Janine Papon
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  3. Mathilde Bonnet
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Correspondence to Nicole Moins.

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Gardette, M., Papon, J., Bonnet, M. et al. Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter. Invest New Drugs 29, 1253–1263 (2011). https://doi.org/10.1007/s10637-010-9471-x

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  • DOI: https://doi.org/10.1007/s10637-010-9471-x

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