DOI: 10.1073/pnas.93.26.15481. 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

10.1073/pnas.93.26.15481

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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.

Bibliography

Monia, B. P., Sasmor, H., Johnston, J. F., Freier, S. M., Lesnik, E. A., Muller, M., Geiger, T., Altmann, K.-H., Moser, H., & Fabbro, D. (1996). Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C- raf kinase supports an antisense mechanism of action inâvivo. Proceedings of the National Academy of Sciences, 93(26), 15481â15484.

Authors 10

Brett P. Monia (first)
Henri Sasmor (additional)
Joseph F. Johnston (additional)
Susan M. Freier (additional)
Elena A. Lesnik (additional)
Marcel Muller (additional)
Thomas Geiger (additional)
Karl-Heinz Altmann (additional)
Heinz Moser (additional)
Doriano Fabbro (additional)

References 20 Referenced 109

10.1021/jm00066a001
10.1146/annurev.pa.36.040196.000543
10.1038/171737a0
10.1038/nm0696-668
10.1016/S0021-9258(19)85268-7
10.1016/S0021-9258(18)55250-9
Bennett C. F. Kornbrust D. Henry S. Dutson S. Hall W. & Jacoby H. I. J. Pharmacol. Exp. Ther. in press.
10.1016/0076-6879(89)80108-9
M Petersheim, D H Turner Biochemistry 31, 12055–12061 (1983). / Biochemistry by Petersheim M (1983)
D M Valenzuela, J Groffen Nucleic Acids Res 14, 844–852 (1985). / Nucleic Acids Res by Valenzuela D M (1985)
, eds F M Ausubel, R Brent, R E Kingston, D D Moore, J G Seidman, J A Smith, K Struhl (Greene & Wiley, New York Current Protocols in Molecular Biology, 1987). / Current Protocols in Molecular Biology by Ausubel F M (1987)
10.1073/pnas.91.24.11762
10.1002/ijc.2910430519
10.1126/science.8351515
10.1089/ard.1995.5.241
10.1038/nm1195-1119
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10.1111/j.1349-7006.1992.tb02734.x
10.1111/j.1348-0421.1994.tb01867.x
10.1074/jbc.270.6.2620

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:34 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 2:38 p.m.)
Indexed	1 month ago (Aug. 2, 2025, 12:20 a.m.)
Issued	28 years, 8 months ago (Dec. 24, 1996)
Published	28 years, 8 months ago (Dec. 24, 1996)
Published Online	28 years, 8 months ago (Dec. 24, 1996)
Published Print	28 years, 8 months ago (Dec. 24, 1996)

Funders 0

None

BibTeX

@article{Monia_1996, title={Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C- raf kinase supports an antisense mechanism of action in vivo}, volume={93}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.93.26.15481}, DOI={10.1073/pnas.93.26.15481}, number={26}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Monia, Brett P. and Sasmor, Henri and Johnston, Joseph F. and Freier, Susan M. and Lesnik, Elena A. and Muller, Marcel and Geiger, Thomas and Altmann, Karl-Heinz and Moser, Heinz and Fabbro, Doriano}, year={1996}, month=dec, pages={15481–15484} }

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