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Ciba Found Symp. 1997;209:107-19; discussion 119-23.

First- and second-generation antisense oligonucleotide inhibitors targeted against human c-raf kinase.

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Isis Pharmaceuticals Inc., Department of Molecular Pharmacology, Carlsbad, CA 92008, USA.


Following extensive screening of more than 50 antisense-designed phosphorothioate oligodeoxynucleotides targeted to human c-raf mRNA, one oligodeoxynucleotide (ISIS 5132/CGP 69846A) was identified as being the most potent inhibitor of c-raf gene expression both in vitro and in vivo. ISIS 5132 is a highly sequence-specific and target-specific inhibitor of c-raf mRNA and protein levels. c-raf inhibition results in dramatic alteration of downstream signalling events within the MAP kinase signalling pathway. Moreover, this oligodeoxynucleotide displays potent antitumour activity against a broad spectrum of tumour types in mouse models and has progressed to Phase I clinical trails. In an effort to identify potential back-up compounds to ISIS 5132, a variety of second-generation 2' sugar modifications have been evaluated for activity against c-raf in cell culture. We have identified a number of second-generation oligonucleotides with improved biophysical characteristics that result in enhanced activity against c-raf in cell culture. Activity enhancement was most pronounced for 2'-O-methoxyethyl-modified oligonucleotides and this modification also resulted in significantly improved antitumour activity in vivo.

[Indexed for MEDLINE]

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