title: Anticancer agents are potent neurotoxins in vitro and in vivo.
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 (5-100 microM), cyclophosphamide (5-100 microM), methotrexate (5-100 microM), vinblastin (0.1-1 microM), or thiotepa (5-100 microM), a concentration-dependent neurotoxic effect was observed. Neurotoxicity was potentiated by nontoxic glutamate concentrations. The N-methyl-D-aspartate receptor antagonist MK 801 (10 microM), the AMPA receptor antagonists GYKI 52466 (10 microM) and NBQX (10 microM), and the pancaspase inhibitor Ac-DEVD-CHO (1 nM) ameliorated neurotoxicity of cytotoxic drugs. To investigate neurotoxicity in vivo, we administered to 7-day-old rats the following: cisplatin (5-15 mg/kg i.p.), cyclophosphamide (200-600 mg/kg i.p.), thiotepa (15-45 mg/kg), or ifosfamide (100-500 mg/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.
authors.affiliation: Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Rzeski
authors.forename: Susanne
authors.initials: S
authors.lastname: Pruskil
authors.forename: Alexander
authors.initials: A
authors.lastname: Macke
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.forename: Anne Katrin
authors.initials: AK
authors.lastname: Reiher
authors.forename: Friederike
authors.initials: F
authors.lastname: Hoerster
authors.forename: Corina
authors.initials: C
authors.lastname: Jansma
authors.forename: Bozena
authors.initials: B
authors.lastname: Jarosz
authors.forename: Vanya
authors.initials: V
authors.lastname: Stefovska
authors.forename: Petra
authors.initials: P
authors.lastname: Bittigau
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents