Nucleoside analogues: mechanisms of drug resistance and reversal strategies

Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disord ers (fludarabine, cladribine) and are also used in the treatment of some so lid tumors (gemcitabine). These important compounds share some general comm on characteristics, namely in terms of requiring transport by specific memb rane transporters, metabolism and interaction with intracellular targets. H owever, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interac tion with certain targets which may explain why some compounds are more eff ective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data co ncerning mechanisms of action of and resistance to NA, with particular emph asis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the indu ction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expre ssion of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.