Platinum-induced neurotoxicity and preventive strategies: Past, present, and future

Avan, A. and Postma, T. J. and Ceresa, C. and Avan, A. and Cavaletti, G. and Giovannetti, E. and Peters, G. J. (2015) Platinum-induced neurotoxicity and preventive strategies: Past, present, and future. Oncologist, 20 (4). pp. 411-432.

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Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution. © AlphaMed Press 2015.

Item Type: Article
Additional Information: Cited By :101 Export Date: 16 February 2020 CODEN: OCOLF Correspondence Address: Peters, G.J.; Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, Netherlands; email:
Uncontrolled Keywords: Models Neurotoxicity Pathogenesis Platinum Polymorphism Prevention amifostine antioxidant carboplatin chelating agent cisplatin electrolyte nerve growth factor neuroprotective agent oxaliplatin retinoic acid sodium thiosulfate voltage gated sodium channel antineoplastic agent platinum derivative apoptosis Article clinical feature diagnostic procedure disease course DNA adduct DNA repair enzyme immobilization human meta analysis (topic) neuroprotection pathophysiology peripheral neuropathy pharmacogenetics priority journal randomized controlled trial (topic) treatment response genetic polymorphism Neurotoxicity Syndromes Antineoplastic Agents Humans Neuroprotective Agents Platinum Compounds Polymorphism, Genetic
Subjects: QV pharmacology
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib5 lib5
Date Deposited: 11 May 2020 05:59
Last Modified: 11 May 2020 05:59

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