Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies

doi:10.1016/S0165-6147(98)01253-X

Trends in Pharmacological Sciences

Volume 19, Issue 10, 1 October 1998, Pages 424-430

https://doi.org/10.1016/S0165-6147(98)01253-X Get rights and content

Abstract

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.

Section snippets

Bioavailability and mode of action of nucleoside analogues used in AIDS therapy

The best strategy for AIDS treatment involves a combined therapy using inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) and proteases[1]. Some, but not all, of the inhibitors of viral reverse transcription are nucleoside analogues and, more precisely, 2′,3′-dideoxynucleosides.

Zidovudine (3′-azido-2′,3′-dideoxythymidine), also known as AZT, was the first nucleoside analogue approved for AIDS treatment. The growing list of antiviral nucleoside derivatives includes a

Nucleoside analogues and transport function

Can the sensitivity of a cell to a nucleoside analogue be explained by the type of carrier isoforms that it expresses? Will treatment with nucleoside derivatives modify the pattern of isoform carrier expression? On the basis of previous evidence, the likely answer for both questions is yes, although extensive work is still required to confirm this, especially now that the appropriate molecular tools are becoming available.

Sensitivity of different leukaemia cells to ara-C correlates with the

Conclusions and future perspectives: nucleoside carriers as therapeutic targets

In summary, the bioavailability of nucleoside derivatives could be the result of a complex interaction between the basal `phenotype' of a cell, in terms of nucleoside carrier isoform expression, the putative changes induced by these drugs on this original `phenotype' and the time-course of changes triggered by cell transformation on the nucleoside transporter pattern during carcinogenesis. The possibility that drugs affect not only carrier expression but the kinetic properties of activating or

Acknowledgements

The authors thank those former and present co-workers who made significant contributions to the work on nucleoside transporters in the laboratory: Bonaventura Ruiz-Montasell, Joan Vicenç Martı́nez-Mas, Mireia Gómez-Angelats, Joan Mercader, Andreu Ferrer-Martı́nez, Belén del Santo, Raquel Valdés and Joı̈o Mata. We also thank Dr Adela Mazo for careful reading and discussion of the manuscript and Robin Rycroft for his editorial help. Work from the authors' laboratory has been funded by

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Trends in Pharmacological Sciences

Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies

Abstract

Section snippets

Bioavailability and mode of action of nucleoside analogues used in AIDS therapy

Nucleoside analogues and transport function

Conclusions and future perspectives: nucleoside carriers as therapeutic targets

Acknowledgements

Mutat. Res.

Toxicol. Appl. Pharmacol.

Leuk. Res.

Int. J. Radiat. Oncol. Biol. Phys.

Biochem. Pharmacol.

Blood

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J. Biol. Chem.

J. Biol. Chem.

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J. Natl. Cancer Inst.

Anticancer Drugs