title: Platinum-induced neurotoxicity and preventive strategies: past, present, and future.
abstract: 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.
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Avan
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Tjeerd J
authors.initials: TJ
authors.lastname: Postma
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ceresa
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Avan
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: Departments of Medical Oncology and Neurology, VU University Medical Center, Amsterdam, The Netherlands; Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy; Department of New Sciences and Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran gj.peters@vumc.nl.
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000175:diagnosis* / Q000209:etiology*; D010597:Pharmacogenetics; D017671:Platinum Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D011110:Polymorphism, Genetic
chemical_list: D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D017671:Platinum Compounds
keywords: Models; Neurotoxicity; Pathogenesis; Platinum; Polymorphism; Prevention