Translocation of Nucleoside Analogs Across the Plasma Membrane in Hematologic Malignancies

Abstract

Nucleoside analogs are currently used in the treatment of various hematologic malignancies due to their ability to induce apoptosis of lymphoid cells. For nucleoside-derived drugs to exert their action, they must enter cells via nucleoside transporters from two gene families, SLC28 and SLC29 (CNT and ENT, respectively). Once inside the cell, these drugs must be phosphorylated to their active forms. In contrast, some members of the ATP-binding cassette (ABC) protein family have been identified as responsible for the efflux of the phosphorylated forms of these nucleoside-derived drugs. Here, we review the main nucleoside analogs used in hematologic malignancies and focus especially on those that are currently used in chronic lymphocytic leukemia (CLL). Moreover, we discuss the pharmacological profile of the nucleoside transporters, which determines the bioavailability of and cell sensitivity to these nucleoside-derived drugs. We also discuss the expression of nucleoside transporters and their activities in CLL as well as the possibility of modulating these transporter activities as a means of modulating intracellular drug availability and, consequently, responsiveness to therapy.

Keywords:

• Chronic lymphocytic leukemia
• nucleoside transporters
• nucleoside analogs

Acknowledgments

Financial support: This work was supported by grants SAF2008-00577, SAF2009-09503, 2009SGR624, and 2009SGR967 (Generalitat de Catalunya) and by the Acción Transversal en Cáncer (CIBER Instituto de Salud Carlos III). P.F.C. was funded by the Juan de la Cierva program.