Nucleoside transporters in chronic lymphocytic leukaemia.
Nucleoside derivatives have important therapeutic activity in chronic lymphocytic leukaemia (CLL). Experimental evidence indicates that in CLL cells most of these drugs induce apoptosis ex vivo, suggesting that programmed cell death is the mechanism of their therapeutic action, relying upon previous uptake and metabolic activation. Although defective apoptosis and poor metabolism often cause resistance to treatment, differential uptake and/or export of nucleosides and nucleotides may significantly modulate intracellular drug bioavailability and, consequently, responsiveness to therapy. Two gene families, SLC28 and SLC29, encode transporter proteins responsible for concentrative and equilibrative nucleoside uptake (CNT and ENT, respectively). Furthermore, selected members of the expanding ATP-binding cassette (ABC) protein family have recently been identified as putative efflux pumps for the phosphorylated forms of these nucleoside-derived drugs, ABCC11 (MRP8) being a good candidate to modulate cell sensitivity to fluoropyrimidines. Sensitivity of CLL cells to fludarabine has also been recently correlated with ENT-type transport function, suggesting that, besides the integrity of apoptotic pathways and appropriate intracellular metabolism, transport across the plasma membrane is also a relevant event during CLL treatment. As long as nucleoside transporter expression in leukaemia cells is not constitutive, the possibility of regulating nucleoside transporter function by pharmacological means may also contribute to improve therapy.