Abstract
Chemotherapy remains mainly used for the treatment of acute myeloid leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine moiety facilitates F14512 selective uptake by tumour cells via the polyamine transport system, a machinery overactivated in cancer cells. F14512 has been characterized as a potent drug candidate and is currently in Phase I clinical trials. Here, we demonstrated marked survival benefit and therapeutic efficacy of F14512 treatments in a series of human AML models, established either from AML cell lines or from patient AML samples. Furthermore, we reported in vitro synergistic anti-leukemic effects of F14512 in combination with cytosine arabinoside (Ara-C), doxorubicin, gemcitabine, bortezomib or SAHA. In vivo combination of suboptimal doses of F14512 with Ara-C also resulted in enhanced anti-leukemic activity. We further showed that F14512 triggered both senescence and apoptosis in vivo in primary AML models, but not autophagy. Overall, these results support the clinical development in onco-hematology of this novel promising drug candidate.
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Acknowledgements
The authors gratefully acknowledge Dr Christian Recher and Cécile Demur for the selection of AML patient samples, as well as Dr Alain Latil for his scientific contribution to this work. We also thank Nathalie Chansard, Sandrine Pourtau, Valérie Cartron, Sabine Roy, Jean-Christophe Blanchet, Jérôme Verdier, Marie-Laure Marionnaud, Karine André, Vanessa Offrete and Stéphane Gras for their skilled technical assistance and Christel Ricome for its valuable data-processing assistance.
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Kruczynski, A., Pillon, A., Créancier, L. et al. F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity. Leukemia 27, 2139–2148 (2013). https://doi.org/10.1038/leu.2013.108
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DOI: https://doi.org/10.1038/leu.2013.108
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