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Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

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Summary

The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.

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Acknowledgments

This work was supported by funds from Centre Oscar Lambret, IRCL (Institut de Recherche contre le Cancer de Lille) and IRPF (Institut de Recherche Pierre Fabre).

Conflict of interest

Arnaud Pillon, Anna Kruczynski, Nicolas Guilbaud and Christian Bailly are employed by Pierre Fabre Medicaments, where the products F14512 and F17073 were synthesized.

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Authors and Affiliations

  1. Pediatric oncology unit, Centre Oscar Lambret, Lille, France

    Pierre Leblond

  2. Antitumoral pharmacology unit, Centre Oscar Lambret, 3, Rue Frédéric Combemale, B.P. 307, Inserm U908, Lille, France

    Pierre Leblond, Elodie Boulet, Christine Bal-Mahieu, Amélie Lansiaux & Samuel Meignan

  3. CRDPF, Institut de Recherche Pierre Fabre, Toulouse, France

    Arnaud Pillon, Anna Kruczynski, Nicolas Guilbaud & Christian Bailly

  4. Department of radiotherapy, Centre Oscar Lambret, Lille, France

    Thierry Sarrazin & Eric Lartigau

Authors
  1. Pierre Leblond
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  2. Elodie Boulet
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  3. Christine Bal-Mahieu
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  4. Arnaud Pillon
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  5. Anna Kruczynski
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  6. Nicolas Guilbaud
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  7. Christian Bailly
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  8. Thierry Sarrazin
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  9. Eric Lartigau
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  10. Amélie Lansiaux
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  11. Samuel Meignan
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Correspondence to Samuel Meignan.

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Leblond, P., Boulet, E., Bal-Mahieu, C. et al. Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.. Invest New Drugs 32, 883–892 (2014). https://doi.org/10.1007/s10637-014-0132-3

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  • DOI: https://doi.org/10.1007/s10637-014-0132-3

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