Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies.
Nucleoside analogues used in cancer and anti-viral therapies interfere with nucleotide metabolism and DNA replication, thus inducing their pharmacological effects. A long-awaited goal in the understanding of the pharmacological properties of these molecules, that is the molecular characterization of nucleoside plasma-membrane transporters, has been achieved very recently. These carrier proteins are encoded by at least two gene families and new isoforms remain to be identified. Direct demonstration of translocation of these drugs by nucleoside transporters has already been provided and most of them can inhibit natural nucleoside transport, probably in a competitive manner. The expression of these genes is clearly tissue-specific and might depend on the differentiated status of a cell. This is relevant because the sensitivity of a cell to a drug can depend on the type of nucleoside carrier expressed, and the drug itself might modulate nucleoside carrier expression. In this article, Marçal Pastor-Anglada, Antonio Felipe and Javier Casado discuss recent studies on the regulation of nucleoside carrier expression and of the molecular determinants of substrate specificity. Better knowledge of these will contribute to an improved design of therapies based on nucleoside derivatives.
Pastor-Anglada
M
M
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Spain.
Felipe
A
A
Casado
F J
FJ
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009705:Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002352:Carrier Proteins; D009705:Nucleosides