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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
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/40902
Page Count: 4
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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.
Proceedings of the National Academy of Sciences of the United States of America © 1996 National Academy of Sciences