Abstract
BackgroundOxaliplatin, 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.Methodology/Principal FindingsSpecifically 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/SignificanceIt 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.
Highlights
Oxaliplatin is a third generation platinum-based chemotherapy effective in the treatment of colorectal cancer [1,2,3]
Clinical Features All patients reported the development of acute neuropathic symptoms following oxaliplatin infusion
The present study represents the first assessment of the doseresponse properties of acute and cumulative oxaliplatin exposure in human axons in vivo
Summary
Oxaliplatin is a third generation platinum-based chemotherapy effective in the treatment of colorectal cancer [1,2,3]. Oxaliplatin treatment is limited by prominent neurotoxicity which develops immediately following infusion and accumulates across treatment [4]. A chronic sensory neuropathy develops, leading to longlasting functional disability [1,4]. 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
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