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/stressactivated 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 platinuminducedperipheral neurotoxicity.Todevelopalternative optionsin 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. The Oncologist 2015;20:411-432 Implications for Practice: Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. This review summarizes preclinical and clinical evidence of pathogenesis and pathophysiology of platinum-induced peripheral neurotoxicity, as well as available evidence of neuroprotective and therapeutic strategies. These data may help to develop alternative options in the treatment of platinuminduced neuropathy, studies on in vitro models, and appropriate trials planning to find the best patient-oriented solution.

Chemotherapy‐induced neuropathies—a growing problem for patients and health care providers

“…Using electrophysiological techniques, peripheral nerve changes are diagnosed as mononeuropathies such as carpal tunnel syndrome or mild to severe sensory and sensorimotor polyneuropathies of axonal origin. Studies suggest that the neurotoxic effects are triggered by drug accumulation in the dorsal root ganglia, causing neuronal dysfunction and apoptosis, thus leading to long‐term, often, irreversible changes in the peripheral nervous system (Avan et al., 2015; Park et al., 2015). …”

“…These symptoms usually occur 30–60 min post infusion and resolve within a couple of days (Argyriou et al., 2013; Avan et al., 2015). The mechanisms underlying these transient neurotoxic effects remain unclear; however, recent studies indicate that they might be a direct result of structural properties of oxaliplatin.…”

“…The mechanisms underlying these transient neurotoxic effects remain unclear; however, recent studies indicate that they might be a direct result of structural properties of oxaliplatin. An oxalate, as part of the oxaliplatin chemical compound, released during oxaliplatin metabolism, binds to calcium through chelation, blocking calcium channels and altering neuronal signal transduction (Avan et al., 2015; McWhinney et al., 2009). …”

“…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 kinase) are the main reasons for peripheral nerve and dorsal root ganglia neuron damage during cisplatin and carboplatin therapy. In case of oxaliplatin, polymorphisms of genes affecting the activity of pivotal metal transporters or voltage‐gated sodium channel genes (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as copper transporters and multidrug resistance‐associated proteins) increase oxaliplatin neurotoxicity and treatment response (Avan et al., 2015). A Japanese study of colorectal cancer patients treated with oxaliplatin‐based chemotherapy estimated the pharmacogenetic correlation between neuropathy and polymorphisms of the excision repair cross‐complementation Group 1 (ERCC1) and glutathione‐S‐transferases pi 1 (GSTP1) genes.…”

Hepatic Tumor Metastases Cause Enhanced PEGylated Liposome Uptake by Kupffer Cells

“…34,35) The dysfunction of ion channels and apoptosis caused by a dysfunction of the mitochondria are considered to be possible etiologies for neurotoxicity. 36) Podratz et al reported that cisplatin, a derivative of l-OHP, inhibited mtDNA replication and induced mitochondrial degradation in vitro and in vivo. 37) As such, the mechanism for mitochondrial toxicity appears not to be specific to neuronal cells, and could also be a cause of toxicity in Kupffer cells.…”