Abstract B186: Preclinical antileukemic activity of F14512, a novel targeted cytotoxic agent

Autor: Anna Kruczynski, Nathalie Chansard, Christian Bailly, Sabrina Pesnel, Thierry Imbert, Nathalie Gallay, Cécile Demur, Yoann Menon, Laurent Créancier, Isabelle Vandenberghe, Christel Ricome, Bruno Gomes, Fabien Marty, Nicolas Guilbaud, Bernard Payrastre, Yves Guminski, Arnaud Pillon, Valérie Cartron, Sandrine Pourtau, Jean-Christophe Blanchet, Alain Le Pape, Christian Recher
Rok vydání: 2009
Předmět:
Zdroj: Molecular Cancer Therapeutics. 8:B186-B186
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-09-b186
Popis: Despite advances in the therapy of acute myeloid leukemia (AML), the majority of patients die from their disease. Therefore, the lack of effective therapy mandates the development of novel compounds to improve the outcome of patients with relapsed and refractory leukemias. F14512 is a potent spermine-epipodophyllotoxin conjugate exploiting the polyamine transport system for tumor cell delivery. In this study, we report the in vivo antitumor activity of F14512 against experimental models of AML cell lines and of patient AML samples. F14512 markedly reduced the growth of HL-60 and U937 cell lines in an in vivo xenotransplantation model, resulting in a highly significant increase of survival of leukemia-bearing mice. Etoposide evaluated concurrently demonstrated only moderate in vivo activity against these models. F14512 induced in vivo apoptosis of HL-60 cells, as shown by caspase-3 activation and PARP cleavage. In an effort to mimic the human disease, we injected approximately 106 AML cells collected from a patient into NOD/SCID mice and allowed them to establish as xenografts for 8 weeks. Subsequent treatment with F14512 was carried out for 2 or 3 weeks followed by the analysis at the end of treatment and 1 week after the end of treatment. Two human AML samples were analyzed. Multiple i.v. administrations of F14512 at 0.32 mg/kg, induced an extensive reduction of the number of leukemic cells in mouse bone marrow and blood (97–99%), assessed by flow cytometry analysis, quantitative RT-PCR and histology. To identify leukemic cells expressing an active polyamine transport system, we developed a functional method based on the measurement of the cellular uptake of a nitrobenzoxadiazole fluorescent probe (F96982) combining the same spermine moiety as F14512. The level of fluorescence emitted by the probe F96982 was high in HL-60 cells as well in the 2 patient AML samples that proved to be sensitive to F14512 in vivo. Collectively, these results demonstrated that F14512 exhibits a marked in vivo antileukemic activity, supporting its clinical development. Phase I clinical trials in onco-hematology are now initiated with this novel promising drug candidate. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B186.
Databáze: OpenAIRE
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