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Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase

Nature Medicine volume 2, pages 668–675 (1996)Cite this article

Abstract

Substantial evidence exists supporting a direct role for raf kinases in the development and maintenance of certain human malignancies. Here we test the potential of phosphorothioate antisense oligodeoxynucleotides targeted against human C–raf–1 kinase to specifically inhibit C–raf–1 kinase gene expression and tumor progression in cell culture and in vivo, using human tumor xenograft mouse models. Treatment of human tumor cells with appropriate phosphorothioate antisense oligodeoxynucleotides led to specific inhibition of C–raf kinase gene expression in cell culture and in vivo at well–tolerated doses. Moreover, oligodeoxynucleotide treatment resulted in potent antiproliferative effects in cell culture and potent antitumor effects in vivo against a variety of tumor types that were highly consistent with an antisense mechanism of action for these compounds. These studies strongly suggest that antisense inhibitors targeted against C–raf–1 kinase may be of considerable value as antineoplastic agents that display activity against a wide spectrum of tumor types at well–tolerated doses.

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Isis Pharmaceuticals, 2280 Faraday Avenue, Carlsbad, California, 92008, USA

    Brett P. Monia & Joseph F. Johnston

  2. Department of Oncology, Ciba-Geigy Limited, CH-4002, Basel, Switzerland

    Thomas Geiger, Marcel Muller & Doriano Fabbro

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  1. Brett P. Monia
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  2. Joseph F. Johnston
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  3. Thomas Geiger
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  4. Marcel Muller
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  5. Doriano Fabbro
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Monia, B., Johnston, J., Geiger, T. et al. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nat Med 2, 668–675 (1996). https://doi.org/10.1038/nm0696-668

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