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Mechanisms Underlying Chemotherapy-Induced Neurotoxicity and the Potential for Neuroprotective Strategies

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Chemotherapy-induced neurotoxicity is a significant complication in the successful treatment of many cancers. Neurotoxicity may develop as a consequence of treatment with platinum analogues (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine) and more recently, thalidomide and bortezomib. Typically, the clinical presentation reflects an axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with features suggestive of nerve hyperexcitability including paresthesia, dysesthesia, and pain. These symptoms may be disabling, adversely affecting activities of daily living and thereby quality of life. The incidence of chemotherapy-induced neurotoxicity appears critically related to cumulative dose and infusion duration, while individual risk factors may also influence the development and severity of neurotoxicity. Differences in structural properties between chemotherapies further contribute to variations in clinical presentation. The mechanisms underlying chemotherapy-induced neurotoxicity are diverse and include damage to neuronal cell bodies in the dorsal root ganglion and axonal toxicity via transport deficits or energy failure. More recently, axonal membrane ion channel dysfunction has been identified, including studies in patients treated with oxaliplatin which have revealed alterations in axonal Na+ channels, suggesting that prophylactic pharmacological therapies aimed at modulating ion channel activity may prove useful in reducing neurotoxicity. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity will inevitably assist in the development of future neuroprotective strategies and in the design of novel chemotherapies with improved toxicity profiles.

Keywords: Chemotherapy; neuropathy; neuroprotection; neurotoxicity; oxaliplatin; platinum; taxane

Document Type: Research Article


Affiliations: Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia.

Publication date: December 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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