title: The role of transporters in the toxicity of nucleoside and nucleotide analogs.
abstract: BACKGROUND
  Two families of nucleoside analogs have been developed to treat viral infections and cancer, but these compounds can cause tissue- and cell-specific toxicity related to their uptake and subcellular activity, which are dictated by host enzymes and transporters. Cellular uptake of these compounds requires nucleoside transporters that share functional similarities but differ in substrate specificity. Tissue-specific cellular expression of these transporters enables nucleoside analogs to produce their tissue-specific toxic effects, a limiting factor in the treatment of retroviruses and cancer.
  
  
  METHODS
  This review discusses the families of nucleoside transporters and how they mediate cellular uptake of nucleoside analogs. Specific focus is placed on examples of known cases of transporter-mediated cellular toxicity and classification of the toxicities resulting. Efflux transporters are also explored as a contributor to analog toxicity and cell-specific effects.
  
  
  CONCLUSIONS
  Efforts to modulate transporter uptake/clearance remain long-term goals of oncologists and virologists. Accordingly, subcellular approaches that either increase or decrease intracellular nucleoside analog concentrations are eagerly sought and include transporter inhibitors and targeting transporter expression. However, additional understanding of nucleoside transporter kinetics, tissue expression and genetic polymorphisms is required to design better molecules and better therapies.
authors.affiliation: Emory University, Pathology, Atlanta, GA 30322, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Koczor
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Torres
authors.forename: William
authors.initials: W
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D001692:Biological Transport; D006801:Humans; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism / Q000633:toxicity*; D033704:Nucleotide Transport Proteins / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D033704:Nucleotide Transport Proteins; D009711:Nucleotides