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Sequence-Specific Antitumor Activity of a Phosphorothioate Oligodeoxyribonucleotide Targeted to Human C-Raf Kinase Supports an Antisense Mechanism of Action in vivo

Brett P. Monia, Henri Sasmor, Joseph F. Johnston, Susan M. Freier, Elena A. Lesnik, Marcel Muller, Thomas Geiger, Karl-Heinz Altmann, Heinz Moser and Doriano Fabbro
Proceedings of the National Academy of Sciences of the United States of America
Vol. 93, No. 26 (Dec. 24, 1996), pp. 15481-15484
Stable URL: http://www.jstor.org/stable/40902
Page Count: 4
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Sequence-Specific Antitumor Activity of a Phosphorothioate Oligodeoxyribonucleotide Targeted to Human C-Raf Kinase Supports an Antisense Mechanism of Action in vivo
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Abstract

To determine the mechanism of action responsible for the in vivo antitumor activity of a phosphorothioate antisense inhibitor targeted against human C-raf kinase (ISIS 5132, also known as CGP69846A), a series of mismatched phosphorothioate analogs of ISIS 5132 or CGP69846A were synthesized and characterized with respect to hybridization affinity, inhibitory effects on C-raf gene expression in vitro, and antitumor activity in vivo. Incorporation of a single mismatch into the sequence of ISIS 5132 or CGP69846A resulted in reduced hybridization affinity toward C-raf RNA sequences and reduced inhibitory activity against C-raf expression in vitro and tumor growth in vivo. Moreover, incorporation of additional mismatches resulted in further loss of in vitro and in vivo activity in a manner that correlated well with a hybridization-based (i.e., antisense) mechanism of action. These results provide important experimental evidence supporting an antisense mechanism of action underlying the in vivo antitumor activity displayed by ISIS 5132 or CGP69846A.

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