Investigational New Drugs

, Volume 32, Issue 4, pp 587–597

Evaluation of two 125I-radiolabeled acridine derivatives for Auger-electron radionuclide therapy of melanoma

  • Maryline Gardette
  • Claire Viallard
  • Salomé Paillas
  • Jean-Luc Guerquin-Kern
  • Janine Papon
  • Nicole Moins
  • Pierre Labarre
  • Nicolas Desbois
  • Pascal Wong-Wah-Chung
  • Sabine Palle
  • Ting-Di Wu
  • Jean-Pierre Pouget
  • Elisabeth Miot-Noirault
  • Jean-Michel Chezal
  • Francoise Degoul
PRECLINICAL STUDIES

DOI: 10.1007/s10637-014-0086-5

Cite this article as:
Gardette, M., Viallard, C., Paillas, S. et al. Invest New Drugs (2014) 32: 587. doi:10.1007/s10637-014-0086-5

Summary

We previously selected two melanin-targeting radioligands [125I]ICF01035 and [125I]ICF01040 for melanoma-targeted 125I radionuclide therapy according to their pharmacological profile in mice bearing B16F0 tumors. Here we demonstrate in vitro that these compounds present different radiotoxicities in relation to melanin and acidic vesicle contents in B16F0, B16F0 PTU and A375 cell lines. ICF01035 is effectively observed in nuclei of achromic (A375) melanoma or in melanosomes of melanized melanoma (B16F0), while ICF01040 stays in cytoplasmic vesicles in both cells. [125I]ICF01035 induced a similar survival fraction (A50) in all cell lines and led to a significant decrease in S-phase cells in amelanotic cell lines. [125I]ICF01040 induced a higher A50 in B16 cell lines compared to [125I]ICF01035 ones. [125I]ICF01040 induced a G2/M blockade in both A375 and B16F0 PTU, associated with its presence in cytoplasmic acidic vesicles. These results suggest that the radiotoxicity of [125I]ICF01035 and [125I]ICF01040 are not exclusively reliant on DNA alterations compatible with γ rays but likely result from local dose deposition (Auger electrons) leading to toxic compound leaks from acidic vesicles. In vivo, [125I]ICF01035 significantly reduced the number of B16F0 lung colonies, enabling a significant increase in survival of the treated mice. Targeting melanosomes or acidic vesicles is thus an option for future melanoma therapy.

Keywords

Melanoma Melanin Acidic vesicles Targeted radionuclide therapy Auger electron emitter Iodine 125 

Abbreviations

TRT

Targeted radionuclide therapy

ICF01035

N-(2-diethylaminoethyl)-9,10-dihydro-7-iodo-9-oxoacridine-4-carboxamide hydrochloride salt

ICF01040

N-(2-diethylaminoethyl)-5-iodoacridine-4-carboxamide dihydrochloride salt

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Maryline Gardette
    • 1
    • 2
    • 3
  • Claire Viallard
    • 1
    • 2
    • 3
  • Salomé Paillas
    • 4
    • 5
    • 6
  • Jean-Luc Guerquin-Kern
    • 7
    • 8
  • Janine Papon
    • 1
    • 2
    • 3
  • Nicole Moins
    • 1
    • 2
    • 3
  • Pierre Labarre
    • 1
    • 2
    • 3
  • Nicolas Desbois
    • 9
  • Pascal Wong-Wah-Chung
    • 10
  • Sabine Palle
    • 11
  • Ting-Di Wu
    • 7
    • 8
  • Jean-Pierre Pouget
    • 4
    • 5
    • 6
  • Elisabeth Miot-Noirault
    • 1
    • 2
    • 3
  • Jean-Michel Chezal
    • 1
    • 2
    • 3
  • Francoise Degoul
    • 1
    • 2
    • 3
  1. 1.Université d’Auvergne, Imagerie Moléculaire et Thérapie VectoriséeClermont UniversitéClermont-FerrandFrance
  2. 2.Inserm, U 990Clermont-FerrandFrance
  3. 3.Centre Jean PerrinClermont-FerrandFrance
  4. 4.IRCM, Institut de Recherche en Cancérologie de MontpellierMontpellierFrance
  5. 5.INSERM, U896MontpellierFrance
  6. 6.Université Montpellier 1MontpellierFrance
  7. 7.Laboratoire de Microscopie IoniqueInstitut CurieOrsayFrance
  8. 8.INSERM, U759OrsayFrance
  9. 9.ICHUB (UMR6302)Université de BourgogneDijonFrance
  10. 10.CNRS, LCE, FRE 3416, Équipe MPO, Europôle de l’ArboisAix Marseille UniversitéAix-en-Provence Cedex 4France
  11. 11.Centre de Microscopie Confocale MultiphotoniqueUniversité Jean Monnet, Université de Lyon, Pôle Optique et VisionSaint-Etienne Cedex 2France

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