1. ¹INSERM U685, Hôpital Saint-Louis, Institut d'Hématologie, Paris, France
2. ²Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

Correspondence: Dr E Ségal-Bendirdjian, INSERM U685, Institut d'Hématologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux 75475 Paris cedex 10, France. Fax: +33 1 42 40 95 57; E-mail: segal@stlouis.inserm.fr

³These authors contributed equally to this work

Received 3 June 2005; Accepted 19 July 2005; Published online 18 August 2005.

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-RAR 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.