| Popis: |
The ability to rationally design antisense drugs and the theoretical selectivity of these compounds for specific genomic and viral mRNA targets make their use as therapeutic agents extremely attractive. Pharmacologic data emerging from our and other laboratories indicate that some unmodified and backbone modified oligonucleotides may be cytotoxic. In general, cytotoxicity was usually seen at concentrations higher than those required for specific antisense effects. Factors that may modulate the toxicity of phosphorothioates include cell type, various media components including serum, length and method of preparation. Pharmacokinetic experiments using phosphodiester, phosphorothioate and methylphosphonate oligonucleotides suggest that these compounds may be taken up and distributed within some cells. Uptake was generally time, temperature, concentration dependent, and required cellular energy. The mechanism of uptake varied according to oligonucleotide type. The in vitro data as well as preliminary in vivo studies demonstrating the safety, antiviral activity and bioavailability of a number of oligonucleotides suggest that these compounds represent a novel therapeutic modality. |
