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To determine the mechanism of action responsible for thein 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 expressionin vitro , and antitumor activityin 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 expressionin vitro and tumor growthin vivo . Moreover, incorporation of additional mismatches resulted in further loss ofin vitro andin 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 thein vivo antitumor activity displayed by ISIS 5132 or CGP69846A.

proceedings of the national academy of sciences of the united states of america

Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C- <i>raf</i> kinase supports an antisense mechanism of action <i>in vivo</i>

Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C- raf kinase supports an antisense mechanism of action in vivo