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Molecular Pharmacology

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Research ArticleArticle

Exposure of Human Vascular Smooth Muscle Cells to Raf-1 Antisense Oligodeoxynucleotides: Cellular Responses and Pharmacodynamic Implications

Christoph Schumacher, Catherine L. Cioffi, Haamid Sharif, William Haston, Brett P. Monia and Lawrence Wennogle
Molecular Pharmacology January 1998, 53 (1) 97-104; DOI: https://doi.org/10.1124/mol.53.1.97
Christoph Schumacher
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Catherine L. Cioffi
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Haamid Sharif
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William Haston
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Brett P. Monia
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Lawrence Wennogle
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Abstract

To characterize the pharmacodynamic properties of CGP 69846A/ISIS 5132, an antisense oligodeoxynucleotide directed against the mitogenic signal transducer Raf-1 kinase, we investigated the elicited biological responses in human coronary artery smooth muscle cells. Cell exposure to CGP 69846A resulted in a reversible time- and concentration-dependent down-regulation of cellular Raf-1 gene expression and, ultimately, inhibition of cell cycle progression. The highest potencies of this compound to reduce Raf-1 mRNA and protein levels were observed after 24 and 48 hr of cell exposure, respectively, with corresponding IC50 values of ∼100 and ∼300 nm. Proliferation was inhibited with an IC50value of ∼300 nm after 72 hr. We interpreted the recovery rate of Raf-1 mRNA after cell exposure to antisense ODNs as the half-life (t ½ ∼50 hr) of active intracellular CGP 69846A in our cell culture system. The endogenous Raf-1 turnover half-life of ∼30 hr, as assessed by monitoring metabolically labeled Raf-1 protein, correlated kinetically with the antisense-induced protein decay rate (50% decay in ∼33 hr), indicating that the efficiency of CGP 69846A in decreasing Raf-1 protein levels was rate-limited by the endogenous protein turnover rate. The pharmacodynamic effects of CGP 69846A antisense ODNs are therefore limited by the duration of its intracellular activity rather than by its ability to transiently decrease mRNA levels. Local steady state exposure to CGP 69846A may represent a new approach to prevent the transition of quiescent vascular smooth muscle cells into the pathologically hyperproliferating cells seen after angioplasty.

Footnotes

    • Received July 23, 1997.
    • Accepted October 6, 1997.
  • Send reprint requests to: Christoph Schumacher, Ph.D., Research Department, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901. E-mail:christopher.schumacher{at}pharma.novartis.com

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (1)
Molecular Pharmacology
Vol. 53, Issue 1
1 Jan 1998
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Research ArticleArticle

Exposure of Human Vascular Smooth Muscle Cells to Raf-1 Antisense Oligodeoxynucleotides: Cellular Responses and Pharmacodynamic Implications

Christoph Schumacher, Catherine L. Cioffi, Haamid Sharif, William Haston, Brett P. Monia and Lawrence Wennogle
Molecular Pharmacology January 1, 1998, 53 (1) 97-104; DOI: https://doi.org/10.1124/mol.53.1.97

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Research ArticleArticle

Exposure of Human Vascular Smooth Muscle Cells to Raf-1 Antisense Oligodeoxynucleotides: Cellular Responses and Pharmacodynamic Implications

Christoph Schumacher, Catherine L. Cioffi, Haamid Sharif, William Haston, Brett P. Monia and Lawrence Wennogle
Molecular Pharmacology January 1, 1998, 53 (1) 97-104; DOI: https://doi.org/10.1124/mol.53.1.97
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