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Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides.

Publication ,  Journal Article
Vaughn, JP; Stekler, J; Demirdji, S; Mills, JK; Caruthers, MH; Iglehart, JD; Marks, JR
Published in: Nucleic Acids Res
November 15, 1996

Antisense activity against erbB-2 of a variety of sulfur-modified oligonucleotides was examined in a breast cancer cell line which overexpresses this oncogene. Using a 15 base anti-erbB-2 sequence previously shown to be effective, various backbone configurations containing phosphoromonothioate or phosphorodithioate linkages were evaluated for antisense activity by a two-color flow cytometric assay. This sequence was effective in inhibiting the production of erbB-2 protein when it was configured as a monothioate at each linkage and as an alternating dithioate/phosphodiester. Both of these compounds were also able to specifically inhibit erbB-2 mRNA expression, indicative of RNase H-mediated activity. The same sequence protected by either three dithioate or three monothioate linkages at each end was ineffective as an antisense reagent, suggesting that endonuclease activity is a significant determinant of the stability of oligonucleotides. Finally, the erbB-2 sequence target was shifted in an effort to improve antisense activity. A new lead sequence was identified that was significantly more effective in inhibiting erbB-2 protein levels and retained activity at lower concentrations.

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Published In

Nucleic Acids Res

DOI

ISSN

0305-1048

Publication Date

November 15, 1996

Volume

24

Issue

22

Start / End Page

4558 / 4564

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Receptor Protein-Tyrosine Kinases
  • Oligonucleotides, Antisense
  • Molecular Sequence Data
  • Humans
  • Flow Cytometry
  • Female
  • Developmental Biology
 

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Vaughn, J. P., Stekler, J., Demirdji, S., Mills, J. K., Caruthers, M. H., Iglehart, J. D., & Marks, J. R. (1996). Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides. Nucleic Acids Res, 24(22), 4558–4564. https://doi.org/10.1093/nar/24.22.4558
Vaughn, J. P., J. Stekler, S. Demirdji, J. K. Mills, M. H. Caruthers, J. D. Iglehart, and J. R. Marks. “Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides.Nucleic Acids Res 24, no. 22 (November 15, 1996): 4558–64. https://doi.org/10.1093/nar/24.22.4558.
Vaughn JP, Stekler J, Demirdji S, Mills JK, Caruthers MH, Iglehart JD, et al. Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides. Nucleic Acids Res. 1996 Nov 15;24(22):4558–64.
Vaughn, J. P., et al. “Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides.Nucleic Acids Res, vol. 24, no. 22, Nov. 1996, pp. 4558–64. Pubmed, doi:10.1093/nar/24.22.4558.
Vaughn JP, Stekler J, Demirdji S, Mills JK, Caruthers MH, Iglehart JD, Marks JR. Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides. Nucleic Acids Res. 1996 Nov 15;24(22):4558–4564.
Journal cover image

Published In

Nucleic Acids Res

DOI

ISSN

0305-1048

Publication Date

November 15, 1996

Volume

24

Issue

22

Start / End Page

4558 / 4564

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Receptor Protein-Tyrosine Kinases
  • Oligonucleotides, Antisense
  • Molecular Sequence Data
  • Humans
  • Flow Cytometry
  • Female
  • Developmental Biology