Review of in vivo pharmacokinetics and toxicology of phosphorothioate oligonucleotides

Srinivasan, Shashi K.; Iversen, Patrick L.

doi:10.1002/jcla.1860090210

Cited by 110 publications

(48 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We anticipate that a substantial increase in the intracellular efficacy of triplex-induced effects will be achieved (i) by chemical modifications of the oligonucleotide that could improve triplex stability (for example, phosphoramidate oligonucleotides (19,25) or (ii) by delivery methods enhancing cellular uptake after systemic or topical applications of the oligonucleotide, still a major issue in oligonucleotide-based developments (1,13,35,36). Of note, the topical delivery to the skin of oligonucleotides using suitable vehicles, e.g.…”

Section: Discussionmentioning

confidence: 99%

Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides

Besch

Giovannangéli

Kammerbauer

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Selected sequences in the DNA double helix can be specifically recognized by oligonucleotides via hydrogen bonding interactions. The resulting triple helix can modulate DNA metabolism and especially interfere with transcription in a gene-specific manner. To explore the potential of triplex-forming oligonucleotides (TFOs) as gene repressors, a TFO was designed to target a 16-bp sequence within the third intron of the human intercellular-adhesion molecule-1 (ICAM-1) gene, which plays a key role in initiating inflammation. TFO binding to its ICAM-1 target sequence was characterized in vitro and also demonstrated in cell nuclei with the set-up of a novel magnetic capture assay, which represents a general experimental approach to the detection of specific TFO binding and to the determination of the accessibility of a given genomic DNA locus. In a human keratinocyte cell line (A431), we observed that: (i) the ICAM-1 target sequence in the chromatin context within the nuclei is still available for triplex formation and (ii) TFO inhibits sequence and gene-specific interferon-␥-induced ICAM-1 surface expression. Collectively, the data demonstrate effective and specific inhibition of ICAM-1 expression by TFO treatment and support the view that triplex-mediated gene targeting might be a valuable technique for anti-inflammatory or anticancer strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides

Besch

Giovannangéli

Kammerbauer

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…22 Liver enzymes may also be increased in animals treated with moderate to high doses. Several phosphorothioate ODN have been shown to cause acute hypotensive events in monkeys, 23,24 probably due to complement activation. 25 This toxicity can be avoided by giving intravenous infusions rather than bolus injections.…”

Section: Discussionmentioning

confidence: 99%