title: Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity.
abstract: BACKGROUND
  Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction.
  
  
  RESULTS
  Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05).
  
  
  CONCLUSIONS
  It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Susanna B
authors.initials: SB
authors.lastname: Park
authors.forename: Cindy S-Y
authors.initials: CS
authors.lastname: Lin
authors.forename: Arun V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Michael L
authors.initials: ML
authors.lastname: Friedlander
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009498:Neurotoxins / Q000009:adverse effects*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects*; D000077150:Oxaliplatin; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D009498:Neurotoxins; D009944:Organoplatinum Compounds; D015222:Sodium Channels; D000077150:Oxaliplatin