Advertisement

Investigational New Drugs

, Volume 32, Issue 5, pp 883–892 | Cite as

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

  • Pierre Leblond
  • Elodie Boulet
  • Christine Bal-Mahieu
  • Arnaud Pillon
  • Anna Kruczynski
  • Nicolas Guilbaud
  • Christian Bailly
  • Thierry Sarrazin
  • Eric Lartigau
  • Amélie Lansiaux
  • Samuel MeignanEmail author
PRECLINICAL STUDIES

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.

Keywords

Pediatric high grade glioma Neuroblastoma Polyamine transport system F14512 Topoisomerase II inhibitor 

Notes

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.

References

  1. 1.
    Jones C, Perryman L, Hargrave D (2012) Paediatric and adult malignant glioma: close relatives or distant cousins? Nat Rev Clin Oncol 9(7):400–413CrossRefPubMedGoogle Scholar
  2. 2.
    Ladenstein R, Poetschger U, Luksch R, Brock P, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, Forjaz De Lacerda A, Beck Popovic M, Bician P, Garami M, Trahair T, Pearson A, Valteau Couanet D (2011) Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial. J Clin Oncol (Meeting Abstracts) 29 (18_suppl 2)Google Scholar
  3. 3.
    Pegg AE (1988) Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res 48(4):759–774PubMedGoogle Scholar
  4. 4.
    Casero RA Jr, Woster PM (2009) Recent advances in the development of polyamine analogues as antitumor agents. J Med Chem 52(15):4551–4573PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Barret JM, Kruczynski A, Vispe S, Annereau JP, Brel V, Guminski Y, Delcros JG, Lansiaux A, Guilbaud N, Imbert T, Bailly C (2008) F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system. Cancer Res 68(23):9845–9853CrossRefPubMedGoogle Scholar
  6. 6.
    Gentry AC, Pitts SL, Jablonsky MJ, Bailly C, Graves DE, Osheroff N (2011) Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage. Biochemistry 50(15):3240–3249PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Annereau JP, Brel V, Dumontet C, Guminski Y, Imbert T, Broussas M, Vispe S, Breand S, Guilbaud N, Barret JM, Bailly C (2010) A fluorescent biomarker of the polyamine transport system to select patients with AML for F14512 treatment. Leuk Res 34(10):1383–1389CrossRefPubMedGoogle Scholar
  8. 8.
    Kruczynski A, Vandenberghe I, Pillon A, Pesnel S, Goetsch L, Barret JM, Guminski Y, Le Pape A, Imbert T, Bailly C, Guilbaud N (2011) Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system. Invest New Drugs 29(1):9–21CrossRefPubMedGoogle Scholar
  9. 9.
    Kruczynski A, Pillon A, Creancier L, Vandenberghe I, Gomes B, Brel V, Fournier E, Annereau JP, Currie E, Guminski Y, Bonnet D, Bailly C, Guilbaud N (2013) F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity. LeukemiaGoogle Scholar
  10. 10.
    De Botton S, Berthon C, Bulabois C, Prebet T, Vey N, Chevallier P (2012) F14512 a novel polyamine-vectorized anti-cancer drug targeting topoisomerase II in adults patients with acute myeloid leukemia (AML): results from a Phase 1 study. EHA 17th Congress, Amsterdam, pp 14–17Google Scholar
  11. 11.
    De Botton S, Quesnel B, Audoly L, Bailly C, Brandely-Talbol M, Provendier O, Bahleda R, Soria J (2014) Tackling leukemia: Phase 1 study of F14512 in relapsed or refractory AML patients. 12th International Congress on Targeted Anticancer Therapies, WashingtonGoogle Scholar
  12. 12.
    Bax DA, Little SE, Gaspar N, Perryman L, Marshall L, Viana-Pereira M, Jones TA, Williams RD, Grigoriadis A, Vassal G, Workman P, Sheer D, Reis RM, Pearson AD, Hargrave D, Jones C (2009) Molecular and phenotypic characterisation of paediatric glioma cell lines as models for preclinical drug development. PLoS ONE 4(4):e5209PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Kruczynski A, Colpaert F, Tarayre JP, Mouillard P, Fahy J, Hill BT (1998) Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid. Cancer Chemother Pharmacol 41(6):437–447CrossRefPubMedGoogle Scholar
  14. 14.
    Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55CrossRefPubMedGoogle Scholar
  15. 15.
    Chastagner P, Bouffet E, Grill J, Kalifa C (2001) What have we learnt from previous phase II trials to help in the management of childhood brain tumours? Eur J Cancer 37(16):1981–1993CrossRefPubMedGoogle Scholar
  16. 16.
    Seiler N, Delcros JG, Moulinoux JP (1996) Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol 28(8):843–861CrossRefPubMedGoogle Scholar
  17. 17.
    Brel V, Annereau JP, Vispe S, Kruczynski A, Bailly C, Guilbaud N (2011) Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II. Biochem Pharmacol 82(12):1843–1852CrossRefPubMedGoogle Scholar
  18. 18.
    Ballot C, Jendoubi M, Kluza J, Jonneaux A, Laine W, Formstecher P, Bailly C, Marchetti P (2012) Regulation by survivin of cancer cell death induced by F14512, a polyamine-containing inhibitor of DNA topoisomerase II. Apoptosis 17(4):364–376CrossRefPubMedGoogle Scholar
  19. 19.
    Guminski Y, Grousseaud M, Cugnasse S, Brel V, Annereau JP, Vispe S, Guilbaud N, Barret JM, Bailly C, Imbert T (2009) Synthesis of conjugated spermine derivatives with 7-nitrobenzoxadiazole (NBD), rhodamine and bodipy as new fluorescent probes for the polyamine transport system. Bioorg Med Chem Lett 19(9):2474–2477CrossRefPubMedGoogle Scholar
  20. 20.
    Mouawad F, Gros A, Rysman B, Bal-Mahieu C, Bertheau C, Horn S, Sarrazin T, Lartigau E, Chevalier D, Bailly C, Lansiaux A, Meignan S (2014) The antitumor drug F14512 enhances cisplatin and ionizing radiation effects in head and neck squamous carcinoma cell lines. Oral Oncol 50(2):113–119CrossRefPubMedGoogle Scholar
  21. 21.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996CrossRefPubMedGoogle Scholar
  22. 22.
    Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F, Brodeur G, Goldstein M, Trent J (1983) Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 305(5931):245–248CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Pierre Leblond
    • 1
    • 2
  • Elodie Boulet
    • 2
  • Christine Bal-Mahieu
    • 2
  • Arnaud Pillon
    • 3
  • Anna Kruczynski
    • 3
  • Nicolas Guilbaud
    • 3
  • Christian Bailly
    • 3
  • Thierry Sarrazin
    • 4
  • Eric Lartigau
    • 4
  • Amélie Lansiaux
    • 2
  • Samuel Meignan
    • 2
    Email author
  1. 1.Pediatric oncology unitCentre Oscar LambretLilleFrance
  2. 2.Antitumoral pharmacology unitCentre Oscar LambretLilleFrance
  3. 3.CRDPF, Institut de Recherche Pierre FabreToulouseFrance
  4. 4.Department of radiotherapyCentre Oscar LambretLilleFrance

Personalised recommendations