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The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs

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Abstract

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 anti-cancer 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.

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Authors and Affiliations

  1. Membrane Protein Research Group, University of Alberta, Edmonton, AB, Canada

    Jing Zhang, Frank Visser, Karen M. King, James D. Young & Carol E. Cass

  2. Department of Oncology, Cross Cancer Institute, 11560 University Ave., Edmonton, AB, T6G 1Z2, Canada

    Jing Zhang, Frank Visser, Karen M. King & Carol E. Cass

  3. Department of Physiology, Univeristy of Alberta, Edmonton, AB, T6G 2H7, Canada

    James D. Young

  4. Astbury Centre for Structural Molecular Biology, Institute for Membrane and Systems Biology, University of Leeds, Leeds, LS2 9JT, UK

    Stephen A. Baldwin

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  1. Jing Zhang
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Correspondence to Carol E. Cass.

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Zhang, J., Visser, F., King, K.M. et al. The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs. Cancer Metastasis Rev 26, 85–110 (2007). https://doi.org/10.1007/s10555-007-9044-4

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