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The Journal of Neurophysiology Vol. 85 No. 5 May 2001, pp. 2293-2297
Copyright ©2001 by the American Physiological Society
RAPID COMMUNICATION
1Laboratoire de Neurophysiologie Unité Propre de Recherche de l'Enseignement Supérieur Equipe d'Accueil (UPRES EA) 2647, Université d'Angers, Unité de Formation et de Recherche (UFR) Sciences, F-49045 Angers Cedex; and 2Laboratoire de Biologie Moléculaire, Immunologie et Thérapeutique des Cancers (BMITC), Centre Paul Papin, Centre Hospitalier Universitaire d'Angers, F-49033 Angers Cedex, France
Grolleau, Françoise,
Laurence Gamelin,
Michèle Boisdron-Celle,
Bruno Lapied,
Marcel Pelhate, and
Erick Gamelin.
A Possible Explanation for a Neurotoxic Effect of the Anticancer
Agent Oxaliplatin on Neuronal Voltage-Gated Sodium
Channels. J. Neurophysiol. 85: 2293-2297, 2001. Oxaliplatin, a new widely used anticancer drug, displays frequent,
sometimes severe, acute sensory neurotoxicity accompanied by
neuromuscular signs that look like the symptoms observed in tetany and
myotonia. The whole cell patch-clamp technique was employed to
investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons
isolated from the CNS of the cockroach Periplaneta
americana. Within the clinical concentration range, oxaliplatin
(40-500 µM), applied intracellularly, decreased the amplitude of the
voltage-gated sodium current resulting in a reduction of half the
amplitude of the action potential. For comparison, two other platinum
derivatives, cisplatin and carboplatin, were found to be ineffective at
reducing the sodium current amplitude. In addition, we compared the
oxaliplatin action to those of its metabolites
dichloro-diaminocyclohexane platinum
(dach-Cl2-platin) and oxalate. Oxalate (500 µM)
was found to be effective, like oxaliplatin, at reducing the inward
sodium current amplitude, whereas dach-Cl2-platin
(500 µM) failed to change the current amplitude. Interestingly, the
effect of oxalate or oxaliplatin could be mimicked by using
intracellularly applied 10 mM
bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid
(BAPTA), known as chelator of calcium ions. We concluded that
oxaliplatin was capable of altering the voltage-gated sodium channels
through a pathway involving calcium ions probably immobilized by its
metabolite oxalate. The medical interest of preventing acute neurotoxic
side effects of oxaliplatin by infusing Ca2+ and
Mg2+ is discussed.
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