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Differentiation

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

Leukemia volume 19, pages 1806–1811 (2005)Cite this article

Abstract

Acute promyelocytic leukemia (APL) is efficiently treated with a cell differentiation inducer, all-trans retinoic acid (ATRA). However, a significant percentage of patients still develop resistance to this treatment. Recently, arsenic trioxide (As2O3), alone or in combination with ATRA, has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. Previous investigations restricted the mechanism of this synergism to the modulation and/or degradation of PML-RARα oncoprotein through distinct pathways. In this study, using several ATRA maturation-resistant APL cell lines, we demonstrate in vitro that the success of ATRA/As2O3 treatment in APL pathology can be explained, at least in part, by a synergistic effect of these two drugs in triggering downregulation of telomerase efficient enough to cause telomere shortening and subsequent cell death. Such long-term low-dose combinatorial therapy strategies, developed also to avoid acute side effects, reinforce the notion that the antitelomerase strategy, based on a combination of active agents, should now be considered and evaluated not only in APL but also in other malignancies.

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Acknowledgements

This work was supported by INSERM, the Ligue contre le Cancer, the Association pour la Recherche contre le Cancer (ARC nos. 4513 and 3416), and OTKA T-038163 (Hungary) research grant, BIO-00032/2001 Biotechnology Grant and F-1/03 French–Hungarian Bilateral Intergovernmental S&T Cooperation. FP was funded by the Fondation pour la Recherche Médicale (FRM). CD is a research fellow of Association pour la Recherche contre le Cancer. IT is supported by EMBO, the Société Française du Cancer and Société Française d'Hématologie.

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  1. I Tarkanyi and C Dudognon: These authors contributed equally to this work

Authors and Affiliations

  1. INSERM U685, Hôpital Saint-Louis, Institut d'Hématologie, Paris, France

    I Tarkanyi, C Dudognon, J Hillion, F Pendino, M Lanotte & E Ségal-Bendirdjian

  2. Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    I Tarkanyi & J Aradi

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  1. I Tarkanyi
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  2. C Dudognon
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  3. J Hillion
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  4. F Pendino
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Correspondence to E Ségal-Bendirdjian.

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Tarkanyi, I., Dudognon, C., Hillion, J. et al. Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death. Leukemia 19, 1806–1811 (2005). https://doi.org/10.1038/sj.leu.2403923

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