The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs

Nucleoside analogs are important components of treatment regimens for various malignancies. Nucleoside-specific membrane transporters mediate plasma membrane permeation of physiologic nucleosides and most nucleoside analogs, for which the initial event is cellular conversion of nucleosides to active agents. Understanding of the roles of nucleoside transporters in nucleoside drug toxicity and resistance will provide opportunities for potentiating anticancer efficacy and avoiding resistance. Because transportability is a possible determinant of toxicity and resistance of many nucleoside analogs, nucleoside transporter abundance might be a prognostic marker to assess drug resistance. Elucidation of the structural determinants of nucleoside analogs for interaction with transporter proteins as well as the structural features of transporter proteins required for permeant interaction and translocation will lead to "transportability guidelines" for the rational design and therapeutic application of nucleoside analogs as anticancer drugs. It should eventually be possible to develop clinical assays that predict sensitivity and/or resistance to nucleoside anticancer drugs and thus to identify those patient populations that will most likely benefit from optimal nucleoside analog treatments. This review discusses recent results from structure/function studies of human nucleoside transporters, the role of nucleoside transport processes in the cytotoxicity and resistance of several anticancer nucleoside analogs and strategies to improve the nucleoside transporter-related anticancer effects of nucleoside analogs.