Anticancer agents are potent neurotoxins in vitro and in vivo

Authors

  • Wojciech Rzeski PhD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
    2. Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland
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  • Susanne Pruskil MD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
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  • Alexander Macke MD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
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  • Ursula Felderhoff-Mueser MD, PhD,

    1. Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
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  • Anne Katrin Reiher MD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
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  • Friederike Hoerster MD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
    2. Department of Pediatrics, University of Heidelberg Berlin, Germany
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  • Corina Jansma MD,

    1. Department of Pediatrics, Vivantes Hospital Neukölln, Berlin, Germany
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  • Bozena Jarosz MD,

    1. Department of Clinical Pathology, Medical University of Lublin, Lublin, Poland
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  • Vanya Stefovska MD, PhD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
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  • Petra Bittigau MD,

    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
    2. Neuroscience Research Center, Charité, Humboldt University Berlin, Berlin, Germany
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  • Chrysanthy Ikonomidou MD, PhD

    Corresponding author
    1. Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany
    2. Department of Pediatrics, University of Heidelberg Berlin, Germany
    3. Neuroscience Research Center, Charité, Humboldt University Berlin, Berlin, Germany
    • Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
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Abstract

Neurotoxicity of anticancer agents complicates treatment of children with cancer. We investigated neurotoxic effects of common cytotoxic drugs in neuronal cultures and in the developing rat brain. When neurons were exposed to cisplatin (5–100μM), cyclophosphamide (5–100μM), methotrexate (5–100μM), vinblastin (0.1–1μM), or thiotepa (5–100μM), a concentration-dependent neurotoxic effect was observed. Neurotoxicity was potentiated by nontoxic glutamate concentrations. The N-methyl-D-aspartate receptor antagonist MK 801 (10μM), the AMPA receptor antagonists GYKI 52466 (10μM) and NBQX (10μM), and the pancaspase inhibitor Ac-DEVD-CHO (1nM) ameliorated neurotoxicity of cytotoxic drugs. To investigate neurotoxicity in vivo, we administered to 7-day-old rats the following: cisplatin (5–15mg/kg IP), cyclophosphamide (200–600mg/kg IP), thiotepa (15–45mg/kg), or ifosfamide (100–500mg/kg) and their brains were analyzed at 4 to 24 hours. Cytotoxic drugs produced widespread lesions within cortex, thalamus, hippocampal dentate gyrus, and caudate nucleus in a dose-dependent fashion. Early histological analysis demonstrated dendritic swelling and relative preservation of axonal terminals, which are morphological features indicating excitotoxicity. After longer survival periods, degenerating neurons displayed morphological features consistent with active cell death. These results demonstrate that anticancer drugs are potent neurotoxins in vitro and in vivo; they activate excitotoxic mechanisms but also trigger active neuronal death. Ann Neurol 2004

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