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Pharmacological properties of the ornithine decarboxylase inhibitor 3-aminooxy-1-propanamine and several structural analogues

  • Original Articles
  • Ornithine Decarboxylase, Inhibitors, Mechanism of Action
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Abstract

Analogues of 3-aminooxy-1-propanamine proved to be highly potent and selective inhibitors of ornithine decarboxylase (ODC). The compounds competed with ornithine for the substrate binding site of ODC, but resulted in progressive and apparently irreversible inactivation of the enzyme. Diamine oxidase was inhibited by these compounds to a lesser extent than ODC; the compounds were not metabolized by this enzyme. Several derivatives were growth-inhibitory for human T24 cells and for other mammalian cells, the most active compound being 3-aminooxy-2-fluoro-1-propanamine (AFPA). Growth-arrested cells were largely depleted of putrescine and spermidine. Cellular growth arrest could be antagonized by supplementation with spermidine. Selection for resistance against AFPA led to cells with amplified ODC genes and overexpression of the message. Some of the derivatives were tumoristatic at well-tolerated doses in mice bearing solid T24 tumours. The antiproliferative activity of these compounds appears to be mediated by polyamine depletion.

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Authors and Affiliations

  1. Research Laboratories, Pharmaceuticals Division, Ciba-Geigy Ltd., K-125.4.01, CH-4002, Basel, Switzerland

    Helmut Mett, Jaroslav Stanek, Jörg Frei & Urs Regenass

  2. Department of Biochemistry, University of Murcia, Spain

    Juan A. Lopez-Ballester

  3. Department of Biochemistry and Biotechnology, University of Kuopio, SF-70211, Kuopio, Finland

    Juhani Jänne, Leena Alhonen & Riita Sinervirta

Authors
  1. Helmut Mett
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  2. Jaroslav Stanek
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  4. Juhani Jänne
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  7. Jörg Frei
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  8. Urs Regenass
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Mett, H., Stanek, J., Lopez-Ballester, J.A. et al. Pharmacological properties of the ornithine decarboxylase inhibitor 3-aminooxy-1-propanamine and several structural analogues. Cancer Chemother. Pharmacol. 32, 39–45 (1993). https://doi.org/10.1007/BF00685874

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