Anticancer agents are potent neurotoxins in vitro and in vivo

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), v...

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Bibliographic Details
Published in:	Annals of neurology Vol. 56; no. 3; pp. 351 - 360
Main Authors:	Rzeski, Wojciech, Pruskil, Susanne, Macke, Alexander, Felderhoff-Mueser, Ursula, Reiher, Anne Katrin, Hoerster, Friederike, Jansma, Corina, Jarosz, Bozena, Stefovska, Vanya, Bittigau, Petra, Ikonomidou, Chrysanthy
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-09-2004 Willey-Liss
Subjects:	Animals Antineoplastic Agents - toxicity Biological and medical sciences Cell Death - drug effects Cell Death - physiology Cells, Cultured Cerebral Cortex - drug effects Cerebral Cortex - pathology Cerebral Cortex - physiology Dose-Response Relationship, Drug Medical sciences Neurology Neurons - drug effects Neurons - pathology Rats Rats, Wistar Antineoplastic agent Toxin Nervous system diseases In vitro Neurotoxin
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Summary:	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
Bibliography:	istex:307707A3DBBC99769302D5CE46841B25C16D3948 ark:/67375/WNG-10VD4989-W Dr Emil Alevander Huebner and Gemahlin Stiftung - No. TS 114/03.68/97 ArticleID:ANA20185 Humboldt University ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0364-5134 1531-8249
DOI:	10.1002/ana.20185