Activity of the Polyamine-vectorized Anti-cancer Drug F14512 Against Pediatric Glioma and Neuroblastoma Cell Lines

Overview

Journal Invest New Drugs

Publisher Springer

Specialty Oncology

Date 2014 Jul 11

PMID 25008900

Citations 5

Authors

Pierre Leblond

Elodie Boulet

Christine Bal-Mahieu

Arnaud Pillon

Anna Kruczynski

Nicolas Guilbaud

Christian Bailly

Thierry Sarrazin

Eric Lartigau

Amelie Lansiaux

Samuel Meignan

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Single-cell transcriptome sequencing reveals tumor heterogeneity in family neuroblastoma.

Zhang Y, Ma Y, Liu Q, Du Y, Peng L, Zhou J Front Immunol. 2023; 14:1197773.

PMID: 37790931 PMC: 10543897. DOI: 10.3389/fimmu.2023.1197773.

Phase I dose-escalation study of F14512, a polyamine-vectorized topoisomerase II inhibitor, in patients with platinum-refractory or resistant ovarian cancer.

Leary A, Le Tourneau C, Varga A, Sablin M, Gomez-Roca C, Guilbaud N Invest New Drugs. 2018; 37(4):693-701.

PMID: 30547316 PMC: 6647401. DOI: 10.1007/s10637-018-0688-4.

Spermidine-mediated poly(lactic--glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis.

Tang J, Li J, Li G, Zhang H, Wang L, Li D Int J Nanomedicine. 2017; 12:6687-6704.

PMID: 28932114 PMC: 5598552. DOI: 10.2147/IJN.S140569.

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

Boye P, Serres F, Marescaux L, Hordeaux J, Bouchaert E, Gomes B PLoS One. 2017; 12(5):e0177486.

PMID: 28505195 PMC: 5432161. DOI: 10.1371/journal.pone.0177486.

Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases.

Jain C, Majumder H, Roychoudhury S Curr Genomics. 2017; 18(1):75-92.

PMID: 28503091 PMC: 5321768. DOI: 10.2174/1389202917666160808125213.

References

Bax D, Little S, Gaspar N, Perryman L, Marshall L, Viana-Pereira M . Molecular and phenotypic characterisation of paediatric glioma cell lines as models for preclinical drug development. PLoS One. 2009; 4(4):e5209. PMC: 2666263. DOI: 10.1371/journal.pone.0005209. View

Chastagner P, Bouffet E, Grill J, Kalifa C . What have we learnt from previous phase II trials to help in the management of childhood brain tumours?. Eur J Cancer. 2001; 37(16):1981-93. DOI: 10.1016/s0959-8049(01)00251-9. View

Barret J, Kruczynski A, Vispe S, Annereau J, Brel V, Guminski Y . F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system. Cancer Res. 2008; 68(23):9845-53. DOI: 10.1158/0008-5472.CAN-08-2748. View

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

Pegg A . Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988; 48(4):759-74. View

Jones C, Perryman L, Hargrave D . Paediatric and adult malignant glioma: close relatives or distant cousins?. Nat Rev Clin Oncol. 2012; 9(7):400-13. DOI: 10.1038/nrclinonc.2012.87. View

Kruczynski A, Pillon A, Creancier L, Vandenberghe I, Gomes B, Brel V . F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity. Leukemia. 2013; 27(11):2139-48. DOI: 10.1038/leu.2013.108. View

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

Mouawad F, Gros A, Rysman B, Bal-Mahieu C, Bertheau C, Horn S . The antitumor drug F14512 enhances cisplatin and ionizing radiation effects in head and neck squamous carcinoma cell lines. Oral Oncol. 2013; 50(2):113-9. DOI: 10.1016/j.oraloncology.2013.11.003. View

10.

Kruczynski A, Colpaert F, Tarayre J, Mouillard P, Fahy J, Hill B . Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid. Cancer Chemother Pharmacol. 1998; 41(6):437-47. DOI: 10.1007/s002800050764. View

11.

Gentry A, Pitts S, Jablonsky M, Bailly C, Graves D, Osheroff N . Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage. Biochemistry. 2011; 50(15):3240-9. PMC: 3086367. DOI: 10.1021/bi200094z. View

12.

Kruczynski A, Vandenberghe I, Pillon A, Pesnel S, Goetsch L, Barret J . Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system. Invest New Drugs. 2009; 29(1):9-21. DOI: 10.1007/s10637-009-9328-3. View

13.

Casero Jr R, Woster P . Recent advances in the development of polyamine analogues as antitumor agents. J Med Chem. 2009; 52(15):4551-73. PMC: 2762202. DOI: 10.1021/jm900187v. View

14.

Ballot C, Jendoubi M, Kluza J, Jonneaux A, Laine W, Formstecher P . Regulation by survivin of cancer cell death induced by F14512, a polyamine-containing inhibitor of DNA topoisomerase II. Apoptosis. 2011; 17(4):364-76. DOI: 10.1007/s10495-011-0681-2. View

15.

Guminski Y, Grousseaud M, Cugnasse S, Brel V, Annereau J, Vispe S . 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. 2009; 19(9):2474-7. DOI: 10.1016/j.bmcl.2009.03.052. View

16.

Annereau J, Brel V, Dumontet C, Guminski Y, Imbert T, Broussas M . A fluorescent biomarker of the polyamine transport system to select patients with AML for F14512 treatment. Leuk Res. 2010; 34(10):1383-9. DOI: 10.1016/j.leukres.2009.12.021. View

17.

Schwab M, Alitalo K, Klempnauer K, Varmus H, Bishop J, Gilbert F . Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature. 1983; 305(5931):245-8. DOI: 10.1038/305245a0. View

18.

Seiler N, Delcros J, Moulinoux J . Polyamine transport in mammalian cells. An update. Int J Biochem Cell Biol. 1996; 28(8):843-61. DOI: 10.1016/1357-2725(96)00021-0. View

19.

Brel V, Annereau J, Vispe S, Kruczynski A, Bailly C, Guilbaud N . Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II. Biochem Pharmacol. 2011; 82(12):1843-52. DOI: 10.1016/j.bcp.2011.08.028. View