A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels.
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 microM), 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-Cl(2)-platin) and oxalate. Oxalate (500 microM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl(2)-platin (500 microM) 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 Ca(2+) and Mg(2+) is discussed.
Grolleau
F
F
Laboratoire 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, France. francoise.grolleau@univ-angers.fr
Gamelin
L
L
Boisdron-Celle
M
M
Lapied
B
B
Pelhate
M
M
Gamelin
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D016190:Carboplatin / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003058:Cockroaches; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D017952:Ganglia, Invertebrate / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008274:Magnesium / Q000494:pharmacology / Q000502:physiology; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000494:pharmacology; D010070:Oxalates / Q000494:pharmacology; D000077150:Oxaliplatin; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
D000970:Antineoplastic Agents; D002614:Chelating Agents; D009419:Nerve Tissue Proteins; D009944:Organoplatinum Compounds; D010070:Oxalates; D015222:Sodium Channels; D000077150:Oxaliplatin; C013933:dichloro-1,2-diaminocyclohexane platinum complex; D004533:Egtazic Acid; D012964:Sodium; D016190:Carboplatin; D008274:Magnesium; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002945:Cisplatin; D002118:Calcium