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Antiproliferative Phospholipid Analogues Act via Inhibition of Phosphatidylcholine Biosynthesis

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Frontiers in Bioactive Lipids

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Abstract

In current anticancer therapies most cytostatic agents impair cell division by crosslinking DNA (e.g. cis-platin or alkylating agents), disrupting the cytoskeleton (e.g. vinblastine) or rectifying the cytoskeleton (e.g. taxol). In a new approach to cancer chemotherapy, the cell membrane was described as a target for cytostatic agents 1,2 and it has been proposed that inhibition of cell signaling pathways represents their mode of action3,4. Alkyllysophospholipids, as promising candidates for this kind of cytostatics, possess antineoplastic properties in vitro and in vivo5, leading to the development of another class of antiproliferative phospholipid analogues, the alkylphosphocholines. The prototype of these phospholipid analogues, hexadecylphosphocholine (HePC), has been shown to inhibit cell proliferation and tumor growth 6-8. Using radiolabelled HePC9 it was possible to show that more than 95% of this compound is membrane-bound10 thereby confirming cellular membranes as the primary target of HePC. Since the exact mechanism(s) of alkylphospholipid actions still remained obscure we determined their influence on phosphatidylcholine biosynthesis. Phosphatidylcholine is the main phospholipid of cellular membranes of eucaryotic cells and its biosynthesis is mainly governed by the rate-limiting enzyme of the CDP-choline pathway, CTP:phosphocholine cytidylyltransferase (EC 2.7.7.15)11,12 The activity of cytidylyltransferase is regulated by reversible translocation to membranes and the translocation process has been shown to be influenced by various lipids13. Furthermore, reversible phosphorylation seems to be involved in enzyme regulation14,15 and cytidylyltransferase is a substrate for mitogen-activated protein kinases 16,17 However, the following paragraph will concentrate on cytidylyltransferase/lipid interactions.

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Authors and Affiliations

  1. Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany

    Christoph C. Geilen, Thomas Wieder & Constantin E. Orfanos

  2. Department of Molecular Biology and Biochemistry, University Medical Center Benjamin Franklin, The Free University of Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany

    Thomas Wieder

Authors
  1. Christoph C. Geilen
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  2. Thomas Wieder
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  3. Constantin E. Orfanos
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Editors and Affiliations

  1. The George Washington University Medical Center, Washington, D.C., USA

    Jack Y. Vanderhoek

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© 1996 Springer Science+Business Media New York

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Geilen, C.C., Wieder, T., Orfanos, C.E. (1996). Antiproliferative Phospholipid Analogues Act via Inhibition of Phosphatidylcholine Biosynthesis. In: Vanderhoek, J.Y. (eds) Frontiers in Bioactive Lipids. GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5875-0_32

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  • DOI: https://doi.org/10.1007/978-1-4615-5875-0_32

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7694-1

  • Online ISBN: 978-1-4615-5875-0

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