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

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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.

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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

References

  1. Little EG, Eide MJ (2012) Update on the current state of melanoma incidence. Dermatol Clin 30:355–361

    Article  CAS  PubMed  Google Scholar 

  2. Finn L, Markovic SN, Joseph RW (2012) Therapy for metastatic melanoma: the past, present, and future. BMC Med 10:23

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Smalley KS, Aplin AE, Flaherty KT, Hoeller C, Bosserhoff AK, Haass NK, Bosenberg M, Ribas A, Barnhill R, Kudchadkar R, Messina JL (2012) Meeting report from the 2011 International Melanoma Congress, Tampa, Florida. Pigment Cell Melanoma Res 25:E1–E11

    Article  PubMed  Google Scholar 

  4. Davies AJ (2007) Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I(131) tositumomab. Oncogene 26:3614–3628

    Article  CAS  PubMed  Google Scholar 

  5. Miao Y, Quinn TP (2008) Peptide-targeted radionuclide therapy for melanoma. Crit Rev Oncol Hematol 67:213–228

    Article  PubMed Central  PubMed  Google Scholar 

  6. Eberle AN, Bapst JP, Calame M, Tanner H, Froidevaux S (2010) MSH radiopeptides for targeting melanoma metastases. Adv Exp Med Biol 681:133–142

    Article  CAS  PubMed  Google Scholar 

  7. Koch SE, Lange JR (2000) Amelanotic melanoma: the great masquerader. J Am Acad Dermatol 42:731–734

    Article  CAS  PubMed  Google Scholar 

  8. Nikkola J, Vihinen P, Vlaykova T, Hahka-Kemppinen M, Kahari VM, Pyrhonen S (2002) High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma. Int J Cancer 97:432–438

    Article  CAS  PubMed  Google Scholar 

  9. Ghanem N, Altehoefer C, Hogerle S, Nitzsche E, Lohrmann C, Schafer O, Kotter E, Langer M (2005) Detectability of liver metastases in malignant melanoma: prospective comparison of magnetic resonance imaging and positron emission tomography. Eur J Radiol 54:264–270

    Article  PubMed  Google Scholar 

  10. Quinn T, Zhang X, Miao Y (2010) Targeted melanoma imaging and therapy with radiolabeled alpha-melanocyte stimulating hormone peptide analogues. In: G Ital Dermatol Venereol vol 145. Italy, pp 245–258

  11. Link EM (1999) Targeting melanoma with 211At/131I-methylene blue: preclinical and clinical experience. Hybridoma 18:77–82

    Article  CAS  PubMed  Google Scholar 

  12. Bonnet-Duquennoy M, Papon J, Mishellany F, Labarre P, Guerquin-Kern JL, Wu TD, Gardette M, Maublant J, Penault-Llorca F, Miot-Noirault E, Cayre A, Madelmont JC, Chezal JM, Moins N (2009) Targeted radionuclide therapy of melanoma: anti-tumoural efficacy studies of a new 131I-labelled potential agent. Int J Cancer 125:708–716

    Article  CAS  PubMed  Google Scholar 

  13. Bonnet M, Mishellany F, Papon J, Cayre A, Penault-Llorca F, Madelmont JC, Miot-Noirault E, Chezal JM, Moins N (2010) Anti-melanoma efficacy of internal radionuclide therapy in relation to melanin target distribution. Pigment Cell Melanoma Res 23:e1–e11

    Article  CAS  PubMed  Google Scholar 

  14. Joyal JL, Barrett JA, Marquis JC, Chen J, Hillier SM, Maresca KP, Boyd M, Gage K, Nimmagadda S, Kronauge JF, Friebe M, Dinkelborg L, Stubbs JB, Stabin MG, Mairs R, Pomper MG, Babich JW (2010) Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma. Cancer Res 70:4045–4053

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Oriuchi N, Higuchi T, Hanaoka H, Iida Y, Endo K (2005) Current status of cancer therapy with radiolabeled monoclonal antibody. Ann Nucl Med 19:355–365

    Article  CAS  PubMed  Google Scholar 

  16. Chirumamilla A, Travin MI (2011) Cardiac applications of 123I-mIBG imaging. Semin Nucl Med 41:374–387

    Article  PubMed  Google Scholar 

  17. Al-Haj AN, Lobriguito AM, Lagarde CS (2004) Radiation dose profile in 125I brachytherapy: an 8-year review. Radiat Prot Dosim 111:115–119

    Article  CAS  Google Scholar 

  18. Kassis AI, Adelstein SJ (2005) Radiobiologic principles in radionuclide therapy. J Nucl Med 46(Suppl 1):4S–12S

    PubMed  Google Scholar 

  19. Barendswaard EC, Humm JL, O’Donoghue JA, Sgouros G, Finn RD, Scott AM, Larson SM, Welt S (2001) Relative therapeutic efficacy of (125)I- and (131)I-labeled monoclonal antibody A33 in a human colon cancer xenograft. J Nucl Med 42:1251–1256

    CAS  PubMed  Google Scholar 

  20. Ickenstein LM, Edwards K, Sjoberg S, Carlsson J, Gedda L (2006) A novel 125I-labeled daunorubicin derivative for radionuclide-based cancer therapy. Nucl Med Biol 33:773–783

    Article  CAS  PubMed  Google Scholar 

  21. Desbois N, Gardette M, Papon J, Labarre P, Maisonial A, Auzeloux P, Lartigue C, Bouchon B, Debiton E, Blache Y, Chavignon O, Teulade JC, Maublant J, Madelmont JC, Moins N, Chezal JM (2008) Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma. Bioorg Med Chem 16:7671–7690

    Article  CAS  PubMed  Google Scholar 

  22. Gardette M, Papon J, Bonnet M, Desbois N, Labarre P, Wu TD, Miot-Noirault E, Madelmont JC, Guerquin-Kern JL, Chezal JM, Moins N (2010) Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter. Investig New Drugs 29:1253–1263

    Article  Google Scholar 

  23. Svensson SP, Lindgren S, Powell W, Green H (2003) Melanin inhibits cytotoxic effects of doxorubicin and daunorubicin in MOLT 4 cells. Pigment Cell Res 16:351–354

    Article  CAS  PubMed  Google Scholar 

  24. Larsen AK, Escargueil AE, Skladanowski A (2000) Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacol Ther 85:217–229

    Article  CAS  PubMed  Google Scholar 

  25. Duvvuri M, Gong Y, Chatterji D, Krise JP (2004) Weak base permeability characteristics influence the intracellular sequestration site in the multidrug-resistant human leukemic cell line HL-60. J Biol Chem 279:32367–32372, United States

    Article  CAS  PubMed  Google Scholar 

  26. Guerquin-Kern JL, Wu TD, Quintana C, Croisy A (2005) Progress in analytical imaging of the cell by dynamic secondary ion mass spectrometry (SIMS microscopy). Biochim Biophys Acta 1724:228–238

    Article  CAS  PubMed  Google Scholar 

  27. Chen KG, Leapman RD, Zhang G, Lai B, Valencia JC, Cardarelli CO, Vieira WD, Hearing VJ, Gottesman MM (2009) Influence of melanosome dynamics on melanoma drug sensitivity. J Natl Cancer Inst 101:1259–1271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Wolf M, Eskerski H, Bauder-Wust U, Haberkorn U, Eisenhut M (2006) Alkylating benzamides with melanoma cytotoxicity: experimental chemotherapy in a mouse melanoma model. Melanoma Res 16:487–496

    Article  CAS  PubMed  Google Scholar 

  29. Santoro L, Boutaleb S, Garambois V, Bascoul-Mollevi C, Boudousq V, Kotzki PO, Pelegrin M, Navarro-Teulon I, Pelegrin A, Pouget JP (2009) Noninternalizing monoclonal antibodies are suitable candidates for 125I radioimmunotherapy of small-volume peritoneal carcinomatosis. J Nucl Med 50:2033–2041

    Article  PubMed Central  PubMed  Google Scholar 

  30. Wolf M, Bauder-Wust U, Eskerski H, Bauer C, Eisenhut M (2007) Role of acidic cell organelles in the higher nonmelanoma retention of melanoma markers based on N-(2-dialkylaminoethyl)benzamides and the cytotoxicity of alkylating benzamides. Melanoma Res 17:61–73

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The French Ligue Régionale contre le Cancer provided financial sponsorship for this project. The Auvergne Regional Council and the INSERM provided funding for Maryline Gardette’s PhD work. The authors thank the PICT-IBiSA imaging facility in the Institut Curie for allowing us to use the NanoSIMS microprobe.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Université d’Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont Université, BP 10448, 63000, Clermont-Ferrand, France

    Maryline Gardette, Claire Viallard, Janine Papon, Nicole Moins, Pierre Labarre, Elisabeth Miot-Noirault, Jean-Michel Chezal & Francoise Degoul

  2. Inserm, U 990, 63005, Clermont-Ferrand, France

    Maryline Gardette, Claire Viallard, Janine Papon, Nicole Moins, Pierre Labarre, Elisabeth Miot-Noirault, Jean-Michel Chezal & Francoise Degoul

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

    Maryline Gardette, Claire Viallard, Janine Papon, Nicole Moins, Pierre Labarre, Elisabeth Miot-Noirault, Jean-Michel Chezal & Francoise Degoul

  4. IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298, Montpellier, France

    Salomé Paillas & Jean-Pierre Pouget

  5. INSERM, U896, 34298, Montpellier, France

    Salomé Paillas & Jean-Pierre Pouget

  6. Université Montpellier 1, 34298, Montpellier, France

    Salomé Paillas & Jean-Pierre Pouget

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

    Jean-Luc Guerquin-Kern & Ting-Di Wu

  8. INSERM, U759, Orsay, 91405, France

    Jean-Luc Guerquin-Kern & Ting-Di Wu

  9. ICHUB (UMR6302), Université de Bourgogne, BP47870, 21078, Dijon, France

    Nicolas Desbois

  10. CNRS, LCE, FRE 3416, Équipe MPO, Europôle de l’Arbois, Aix Marseille Université, Bâtiment Villemin, BP 80, 13545, Aix-en-Provence Cedex 4, France

    Pascal Wong-Wah-Chung

  11. Centre de Microscopie Confocale Multiphotonique, Université Jean Monnet, Université de Lyon, Pôle Optique et Vision, 42023, Saint-Etienne Cedex 2, France

    Sabine Palle

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  1. Maryline Gardette
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Correspondence to Francoise Degoul.

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Gardette, M., Viallard, C., Paillas, S. et al. Evaluation of two 125I-radiolabeled acridine derivatives for Auger-electron radionuclide therapy of melanoma. Invest New Drugs 32, 587–597 (2014). https://doi.org/10.1007/s10637-014-0086-5

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  • DOI: https://doi.org/10.1007/s10637-014-0086-5

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