Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures.
Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute neurotoxicity is characterized by the rapid onset of cold-induced distal dysesthesia and/or paresthesia. Sensory symptoms may also be accompanied by cold-dependent muscular contractions of the extremities or the jaw. The symptoms, often occurring during or shortly after infusion, are usually transient and mild. A persistent sensory peripheral neuropathy may also develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment. Studies have shown patients with acute sensory symptoms to display little or no axonal degeneration, suggesting a specific effect of oxaliplatin on sensory neurons and/or motor neurons or muscle cells that is not observed with other platinum agents. The similarity of the acute symptoms induced by oxaliplatin with those caused by several drugs or toxins acting on neuronal or muscular ion channels suggests that these symptoms may result from a specific interaction of oxaliplatin with ion channels located in the cellular membrane. Recent data indicate that oxaliplatin may act on specific isoforms of the voltage gated sodium (Na(+)) channel to increase the excitability of sensory neurons, an action inhibited by the Na(+) channel blocker carbamazepine. This contention is supported by recent clinical findings indicating that pharmacologic blockade of Na(+) channels may prevent and/or repress the acute neurotoxicity of oxaliplatin. Although there is no indication at the moment that a common cellular mechanism induces both the acute and the cumulative neurotoxicity of oxaliplatin, controlled clinical trials are currently underway to establish the value of Na(+) channel blockade against both acute and cumulative oxaliplatin neurotoxicities.
Gamelin
Erick
E
Centre Paul Papin, Cedex, Austria.
Gamelin
Laurence
L
Bossi
Laura
L
Quasthoff
Stefan
S
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D032342:Muscle Cells / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D015222:Sodium Channels / Q000187:drug effects*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D015222:Sodium Channels; D000077150:Oxaliplatin