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Honolulu, HI, United States, 2006/10/19 - French and Italian researchers have now come up with a completely new approach to render anticancer and antiviral nucleoside analogues significantly more potent..
Nucleoside analogues, which are a class of therapeutic agents, display significant anticancer or antiviral activity by interfering with DNA synthesis. They work by incorporating into the elongating DNA strands and terminating the extension process. However, they also affect normal cell growth, such as bone marrow cells, so there can be significant toxic effects. Further limitations to their use are relatively poor intracellular diffusion, rapid metabolism, poor absorption after oral use, and the induction of resistance. French and Italian researchers have now come up with a completely new approach to render anticancer and antiviral nucleoside analogues significantly more potent. By linking the nucleoside analogues to squalene, a biochemical precursor to the whole family of steroids, the researchers observed the self-organization of amphiphilic molecules in water. These nanoassemblies exhibited superior anticancer activity in vitro in human cancer cells.
Professor Patrick Couvreur, director of the Physico-chimie, Pharmacotechnie et Biopharmacie department at the Université de Paris-Sud, and a team of researchers from the Università degli Studi di Torino/Italy and the Laboratoire de Neurovirologie in Fontenay-aux-Roses/France, have discovered that the linkage of nucleoside analogues to squalenic acid ("squalenization"), the acyclic isoprenoid chain of squalene, leads to squalenic amphiphilic prodrugs which self-organize in water as nanoassemblies of 100-300 nm, irrespective of the nucleoside analogue used and the location of covalent linkage. Based on these findings they conceived a new strategy to increase the therapeutic index of the nucleoside analogues and to administer them more efficiently.
Couvreur explained the findings to Nanowerk: "Development of this new platform has been first demonstrated with gemcitabine, a major anticancer drug with broad spectrum activity. The nanoassemblies formed by the squalenization of gemcitabine were found about 6 to 8 times more cytotoxic than gemcitabine itself in vitro on two human cancer cell lines and they exhibited in vivo in aggressive leukemia a dramatically higher anticancer effect than gemcitabine (both after intravenous and oral administration)."
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By Michael Berger, Copyright 2006 Nanowerk LLC