Abstract
Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half live, change the biodistribution and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Duplex and multiplex drugs consist of distinct active drugs with different mechanisms of action, which are linked to each other with either a lipid or a phosphodiester. Enzymatic cleavage of such a prodrug inside the cell releases the drug or the phosphorylated form of the drug. Antitumor activity of cytotoxic drugs can also be enhanced by the use of nanoparticles as carriers. Nanoparticles have the advantage of high stability, high carrier capacity, incorporation of hydrophobic and hydrophilic compounds and variable routes of administration. Encapsulating drugs in liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. Nanoparticles and liposomes can be used to target drugs either actively or passively to the tumor. In this review we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy) nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems. We expect that combining different strategies could further increase the efficacy of these compounds.
Keywords: Deoxynucleoside analogs, fluoropyrimidine analogs, drug targeting, nanoparticles, liposomes, lipophilic prodrugs
Current Medicinal Chemistry
Title: Innovations and Opportunities to Improve Conventional (Deoxy)Nucleoside and Fluoropyrimidine Analogs in Cancer
Volume: 16 Issue: 35
Author(s): A. D. Adema, I. V. Bijnsdorp, M. L. Sandvold, H. M. Verheul and G. J. Peters
Affiliation:
Keywords: Deoxynucleoside analogs, fluoropyrimidine analogs, drug targeting, nanoparticles, liposomes, lipophilic prodrugs
Abstract: Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half live, change the biodistribution and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Duplex and multiplex drugs consist of distinct active drugs with different mechanisms of action, which are linked to each other with either a lipid or a phosphodiester. Enzymatic cleavage of such a prodrug inside the cell releases the drug or the phosphorylated form of the drug. Antitumor activity of cytotoxic drugs can also be enhanced by the use of nanoparticles as carriers. Nanoparticles have the advantage of high stability, high carrier capacity, incorporation of hydrophobic and hydrophilic compounds and variable routes of administration. Encapsulating drugs in liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. Nanoparticles and liposomes can be used to target drugs either actively or passively to the tumor. In this review we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy) nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems. We expect that combining different strategies could further increase the efficacy of these compounds.
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Cite this article as:
Adema D. A., Bijnsdorp V. I., Sandvold L. M., Verheul M. H. and Peters J. G., Innovations and Opportunities to Improve Conventional (Deoxy)Nucleoside and Fluoropyrimidine Analogs in Cancer, Current Medicinal Chemistry 2009; 16 (35) . https://dx.doi.org/10.2174/092986709789878229
DOI https://dx.doi.org/10.2174/092986709789878229 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
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