Chemotherapy-induced peripheral neuropathy.

CHAPTER SIXTEEN

Chemotherapy-Induced Peripheral Neuropathy Jill C. Fehrenbacher1 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, Indiana, USA 1 Corresponding author: e-mail address: [email protected]

Contents 1. Chemotherapy-Induced Neuropathy: An Introduction 2. Classes of Chemotherapeutics 2.1 Microtubule-targeting agents 2.2 Platinum-containing agents 2.3 Proteasome inhibitors 2.4 Angiogenesis inhibitors 3. Clinical Assessment of CIPN 4. Experimental Studies: Animal Models of CIPN 5. Experimental Studies: In Vitro Models of CIPN 6. Proposed Mechanisms Underlying CIPN 6.1 Mitochondrial dysfunction 6.2 Nitroxidative stress 6.3 DNA damage 6.4 Ion channel modulation 6.5 Inflammation 6.6 Neurotrophic factors 6.7 Microtubule alterations 7. Challenges to CIPN Research References

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Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is common in patients receiving anticancer treatment and can affect survivability and long-term quality of life of the patient following treatment. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, thermal information, and pain. There is currently a paucity of pharmacological agents to prevent or treat CIPN. The lack of efficacious therapeutics is due, at least in part, to an incomplete understanding of the mechanisms by which chemotherapies alter the sensitivity of sensory neurons. Although the clinical presentation of CIPN can be similar with the various classes of chemotherapeutic agents,

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there are subtle differences, suggesting that each class of drugs might induce neuropathy via different mechanisms. Multiple mechanisms have been proposed to underlie the development and maintenance of neuropathy; however, most pharmacological agents generated from preclinical experiments have failed to alleviate the symptoms of CIPN in the clinic. Further research is necessary to identify the specific mechanisms by which each class of chemotherapeutics induces neuropathy.

1. CHEMOTHERAPY-INDUCED NEUROPATHY: AN INTRODUCTION With considerable advances in the development of anticancer agents over the past 20–30 years, patients diagnosed with cancer are surviving and living longer following treatment.1 With this increase in survival, researchers and patients are now shifting their focus toward a primary side effect of anticancer treatment, chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is an adverse effect following treatment with multiple classes of chemotherapeutics, including platinum drugs, microtubuletargeting agents (MTAs), proteasome inhibitors, and angiogenesis inhibitors. The reported incidence of CIPN varies widely among patients and chemotherapeutic drugs, but often ranges between 30% and 40%.2 CIPN can be painful and persist as a significant disability following anticancer treatment, resulting in a decreased quality of life for survivors. The symptoms of peripheral neuropathy are primarily sensory and can be divided into gain in function manifestations including burning pain, tingling, and hypersensitivity to cold or touch and loss-of-function characteristics including loss of proprioception, decreased perception of vibration and pinprick, and numbness.3–8 Numbness, the loss of vibratory sense, and deep tendon ankle reflexes are some of the first signs of neuropathy in patients receiving chemotherapy treatment, followed by the development of paresthesia and loss of positional sense.7,9,10 The neuropathy induced by chemotherapeutics is thought to be induced by varying degrees of axonopathy.11–13 As such, symptoms develop in a stocking and glove distribution,14 suggesting that sensory neurons with long fibers such as the axons innervating the hands and feet, are especially susceptible to neurotoxic insult. At high doses, the effects of chemotherapeutics on the autonomic and motor nervous systems can be observed,7,8,15,16 but these are not observed frequently and are not thought to mediate the symptoms of CIPN most commonly reported by patients.

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There are a number of factors which can contribute to the development of neuropathy in patients receiving chemotherapy, including dose intensity,17 cumulative dose,9,18 concurrent treatment with other neurotoxic agents,19 and preexisting conditions, such as diabetic- and/or alcohol-induced peripheral neuropathy.14,20–22 The onset and reversibility of CIPN symptoms are variable between different chemotherapeutic classes and are also dependent on the cumulative dose of drug administered. In some cases, neuropathy symptoms may worsen following completion of treatment, and this phenomenon is called coasting.23,24 Resolution of peripheral neuropathy following the discontinuation of chemotherapeutic treatment is quite variable among patients and between the drugs used for treatment, but can also be dependent on the cumulative dose of the chemotherapeutics administered25,26 and on the intensity of the neuropathic symptoms at their peak.26,27 Some patients experience persistent disabling neuropathy for 9–13 years following the cessation of therapy.28,29 There are also some patients who report mild neuropathy during treatment and an absence of neuropathy symptoms following the cessation of drug treatment. Even in these asymptomatic patients, however, objective analyses of neuropathy (standardized examinations or nerve conduction studies) indicate the persistence of neuropathy,30 suggesting long-term effects of chemotherapy. Unfortunately, no established biomarkers have been identified to predict the development, intensity, or reversibility of CIPN.

2. CLASSES OF CHEMOTHERAPEUTICS 2.1 Microtubule-targeting agents Alterations in microtubule dynamics are a common mechanism of blocking mitosis within dividing cells, which lead to subsequent apoptosis in cancer cells,31 and MTAs have been developed and used extensively as anticancer drugs.32 There are two main classes of MTAs, which are compounds that bind directly to the tubulin subunits to alter the dynamic rearrangement of microtubules. Compounds that bind free β-tubulin subunits and prevent polymerization into microtubules are called depolymerizing or destabilizing agents and include vincristine, vinblastine, and vinorelbine.33–35 The other class of MTAs binds polymerized β-tubulin comprising the microtubule polymer and prevents the depolymerization of the microtubule. These agents are called polymerizing or stabilizing agents and include paclitaxel, docetaxel, and the epothilones.36,37 Although they have opposite

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effects on microtubules, both MTA classes interfere with the dynamic rearrangement of microtubules. The taxanes are used as treatments for several types of cancer including breast, ovarian, gastric, and lung cancers.22 The clinical onset of symptoms of neuropathy occurs 3–6 weeks following the first dose of paclitaxel.7 Prior to the development of CIPN, many patients also experience paclitaxelassociated acute pain syndrome which presents as pain in the large axial muscles in the shoulders, pelvis, and thighs.38,39 Importantly, recent patients data indicate that patients with intense pain in the days following paclitaxel infusion have a higher risk for the development of CIPN 3–18 weeks following the first paclitaxel infusion.39,40 This association suggests that acute increases in the excitability and/or sensitivity of nociceptive sensory neurons could underlie the chronic changes in neuronal sensitivity induced by paclitaxel. Many questions remain regarding the mechanisms by which sensitization of one population of somatic sensory neurons (those innervating the muscles) can predict enhanced sensitivity of cutaneous sensory neurons. The vinca alkaloids are used to treat acute lymphocytic leukemia, lymphomas, and neuroblastoma. The onset and incidence of vinca-induced neuropathy are similar to the taxanes; however, the vinca alkaloids are also associated with increases in autonomic neuropathy, which is rarely observed with the taxanes.41–44 The only epothilone currently used to treat cancer is ixabepilone, which is administered to patients with metastatic or locally advanced breast cancer. The incidence, dose dependence, and reversibility of neuropathy with ixabepilone treatment are similar to that of the taxanes and vinca alkaloids.45

2.2 Platinum-containing agents The platinum-derived chemotherapeutics, cisplatin, carboplatin, and oxaliplatin induce intrastrand and interstrand DNA cross-linkage, which causes the denaturation of nuclear and mitochondrial DNA.46 This interaction with DNA results in damage to the mitochondria and subsequent inhibition of ATPase activity, cellular arrest, and ultimate death of cancer cells via apoptosis and necrosis.47 In addition to cross-linkage of DNA, both cisplatin and oxaliplatin increase the intracellular production of reactive oxygen species (ROS),48,49 which may or may not contribute to the anticancer activity of the drugs. Cisplatin is administered to treat bladder, ovarian, and testicular cancer. Patients receiving cisplatin generally develop peripheral neuropathy when the cumulative dose of cisplatin reaches 250–300 mg/m2.6,18 Once


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the dosage of cisplatin exceeds 500–600 mg/m2, almost all patients demonstrate symptoms of neuropathy.50 Carboplatin, utilized for ovarian cancer, does not typically produce a significant neuropathy in patients. Doses of carboplatin up to 300 mg/m2, which are effective for anticancer treatment, elicit only a mild transient neuropathy.51,52 Oxaliplatin is used for the treatment of colon and advanced colorectal cancer. Patients treated with oxaliplatin may experience both acute and chronic peripheral neuropathies. For example, 86% of patients receiving oxaliplatin describe immediate neurological symptoms, including, but not limited to, cold-induced perioral or pharyngolaryngeal dysesthesias, jaw pain, and muscle stiffness/cramping.53,54 Approximately, 50% of patients receiving a cumulative dose of oxaliplatin of 1000 mg/m2 or higher, which is the standard treatment protocol, develop chronic peripheral neuropathy.5,55 As observed with paclitaxel, the incidence and severity of acute neurological symptoms induced by oxaliplatin can predict the incidence and severity of chronic neuropathy induced by oxaliplatin in patients.56

2.3 Proteasome inhibitors Inhibition of the ubiquitin-proteasome pathway is another mechanism that is being utilized to kill cancer cells. The proteasome pathway is the primary mechanism for the elimination of damaged or unneeded endogenous proteins in eukaryotic cells.57 This regulatory pathway is critical for numerous cellular functions, including regulation of the cell cycle and gene transcription. Inhibition of the proteasome, especially in cancer cells, increases the rate of apoptosis.58 Bortezomib is the first proteasome inhibitor to be examined in human clinical studies as an anticancer agent and is currently used to treat multiple myeloma.59 Patients receiving bortezomib generally develop chronic sharp, burning pain of moderate-to-severe intensity, self-reporting pain values of 7.8 0.7 out of 10 on a 10-point VAS scale.60 It is common that dose reductions of bortezomib must be made to accommodate for the development of chronic neuropathy symptoms.61 Bortezomib also induces an autonomic neuropathy in a subset of patients.62

2.4 Angiogenesis inhibitors In the past years, angiogenesis has been highlighted as a potential anticancer target because of the reliance of tumor growth and metastatic spread on the development of a vascular supply (see Ref. 63). Vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) are two proangiogenic

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factors which have been shown to promote tumor angiogenesis.64–66 Bevacizumab and thalidomide are two chemotherapeutics which target the signaling of VEGF and FGF2. Bevacizumab is approved for the treatment of colorectal cancer, glioblastoma, renal cell cancer, and nonsmall cell lung carcinoma, while thalidomide is used for multiple myeloma67 and investigations into efficacy for combination treatment with thalidomide for the treatment of prostate cancer are ongoing.68,69 Bevacizumab is a recombinant, humanized monoclonal antibody, which binds to and neutralizes VEGF, preventing its association with endothelial receptors. The exact anticancer mechanism of thalidomide is still debated, but it has been shown to reduce tumor levels of both VEGF and FGF2 to hinder angiogenesis.70,71 Bevacizumab has not been documented to cause extensive neuropathy as a monotherapy, but reports indicate that coadministration of bevacizumab with oxaliplatin can intensify peripheral neuropathy induced by the platin.72 Thalidomide elicits the development of peripheral neuropathy symptoms in 50% of patients within 4 months of the initiation of thalidomide treatment.73,74

3. CLINICAL ASSESSMENT OF CIPN A limitation to the interpretation of some clinical studies is the subjective nature by which the presence and intensity of neuropathy is determined by the clinicians and patients. There is much debate regarding the proper endpoints to use to determine the severity of neuropathy in patients and the intensity of neuropathy is often difficult to gage. Several grading scales have been developed by the World Health Organization, Eastern Cooperative Oncology Group, and the National Cancer Institute (NCI) to categorize the intensity of symptoms experienced by patients.75–78 Using the newly revised NCI-Common Terminology Criteria for Adverse Events (version 4.0), a grade 1 neuropathy indicates mild or asymptomatic neuropathy with loss of deep tendon reflexes or the presence of paresthesia that do not interfere with daily life, grade 2 indicates a moderate neuropathy with some interference with complex activities of daily living, grade 3 describes severe symptoms of neuropathy that limit everyday activities of daily living, and grade 4 indicates life threatening neuropathy.77–79 A limitation of these neuropathy scales, however, is that they do not provide descriptive data on the quality of neuropathic symptoms, which is especially problematic in a clinical trial setting. To overcome the subjective nature of symptom reporting, a composite measure of peripheral nerve function, the total neuropathy score


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(TNS), was established.19,80,81 The TNS is a tool that clinicians can use to objectively assess neurological endpoints of sensory and motor function in the upper and lower limbs, autonomic symptoms, vibration sensory threshold, sensitivity to pinprick, and changes in deep tendon reflexes or grip strength. In addition to clinical examination findings, the TNS also has a neurophysiological component, in which the conduction velocities in the sural and peroneal nerves are determined and factored into the total score.82 Chemotherapy sometimes induces a decrease in the action potential amplitude (SNAP) and/or conduction velocity (sCV) of sensory nerve fibers, with occasional effects on the compound muscle action potential and conduction velocity of motor nerves (CMAP and mCV, respectively).83–90 A major limitation to sensory neurophysiological studies is that the action potential amplitude and conduction velocity of sensory nerves mostly reflect the function of large-diameter sensory neurons. Dysfunction of small- and medium-diameter nerve fibers, which may contribute heavily to burning pain sensations in CIPN patients, is not detected by the recorded evoked potentials.91 Although neurophysiological outcomes do not always correlate with painful neuropathy symptoms in patients,91,92 thus questioning their relevance for the diagnosis and/or grading of CIPN, recent studies have demonstrated a strong correlation between early changes in oxaliplatininduced changes in neurophysiological outcomes and the severity of neuropathy following discontinuation of drug treatment.83 A consistent pathological finding in patients receiving chemotherapy and exhibiting numbness and loss of vibratory senses is intraepidermal nerve fiber (IENF) loss in the hands and feet. The IENF is comprised of unmyelinated axons from small-diameter sensory neurons.93 Thus, observing the degree of change in intraepidermal innervation has been measured using immunohistochemistry and novel functional techniques to specifically assess small-fiber neuropathy in CIPN patients. These novel techniques include nerve excitability-threshold tracking94 and Doppler flowmetry to determine axon reflex flare areas.95 Evaluating these endpoints is preferable for testing the ability of drugs to prevent the development of functional neuropathy, because they focus the evaluation toward the site of primary damage, the peripheral nervous system. A limitation of these techniques is that structural loss of innervation does not always correlate with the presence of painful neuropathy symptoms in patients.96 In addition, chemotherapeutics are not the only cause of IENF loss; it is also observed with diabetes mellitus,97 HIV infection98, and other nerve damage. Paradoxically, a complete loss of IENF is observed both in patients with persistent pain93 and genetic insensitivity to pain,99 suggesting

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that epidermal innervation does not necessarily correlate with pain values. The question remains whether the degeneration of IENF results from changes in the sensitivity of sensory neurons or whether the IENF damage causes an increase in the sensitivity of nerve fibers, contributing to the primary symptom of neuropathy that burdens cancer patients: pain.

4. EXPERIMENTAL STUDIES: ANIMAL MODELS OF CIPN Experimental animal models have been developed to examine the mechanisms of CIPN following exposure to paclitaxel, vincristine, epothilones, cisplatin, oxaliplatin, bortezomib, or thalidomide. Although these animal models have evolved over time to closely mimic the behavioral and neurophysical symptoms observed in patients receiving chemotherapy, the initial animal studies were performed using high doses of the chemotherapeutic drugs. These high doses of drugs caused sensory neuron death, overt axonal damage and involvement of the motor and autonomic nervous systems,100–103 and produced impairments in pain-like behaviors, decreases in movement and coordination and decreases in nerve conduction velocity in the tail nerve, suggesting a functional decrease in the sensitivity of sensory neurons.104–110 Since a common complaint of patients with CIPN is augmented pain, rather than analgesia, models with high doses of drug do not optimally reflect the patient condition. The second generation of animal models utilizes lower dosage treatment protocols. This low-dose treatment paradigm elicits mechanical and cold hypersensitivity without inducing sensory neuron loss and gross axonal degeneration.106,111,112 However, the newer treatment paradigms still produce similar distal morphological changes as observed in patients receiving drug treatment, such as degeneration of the IENFs.4,113–116 Dose–symptom relationships in patients and animal models will always be complicated by the fact that the sensory neural tissues, including dorsal root ganglia (DRG), nerve roots and nerves, accumulate the chemotherapeutics,6,18,117 thus discontinuation of the drug treatments does not necessarily mean that chemotherapeutic exposure ceases. Accumulation of the drugs in the DRG has been proposed to occur via uptake in the terminals and soma and is enabled by the dense vascularization and high permeability of capillaries which surround the ganglia.118–121 The amount of drug accumulation has functional consequences, as the DRG concentration of drug is related to the degree of clinical neurotoxicity in patients.6 The onset of behavioral changes in preclinical models varies with the type of chemotherapeutic administered (Table 1). With oxaliplatin and

Table 1 Chemotherapeutics associated with the development of peripheral neuropathy Low-dose animal model Anticancer agent class

Agent

Clinical onset of sensory symptoms

Mechanical sensitivity

Cold sensitivity

Heat sensitivity

IENF density

Microtubuletargeting agents

Taxanes

Acute and chronic

"111

"111

"111

#115

Vinca alkaloids

Chronic

"112,140

"140

#112

#115

Epothilones

Chronic

ND

ND

ND

#130

DNA-cross-linking agents

Cisplatin139,144,145

Chronic

"106,128

No change145

",128 No change106

#93

Oxaliplatin

Acute and chronic

"12

"12

No change12

#12

Proteasome inhibitor

Bortezomib

Chronic

"116

"116

No change116

#116

Angiogenesis inhibitors

Thalidomide

Chronic

Animal model not yet developed

Bevacizumab

Chronic

Animal model not yet developed

ND: not determined.

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paclitaxel, some studies show an acute behavioral effect within 60 min, whereas others observe effects at 24–48 h after initial dosing.122–126 Longterm effects generally present around 6–10 days following the first drug injection and persist for at least 3–7 weeks following the last injection.105,127,128 Consistent modalities affected by various chemotherapeutics include mechanical allodynia and cold allodynia.105,106,111,112 Sensitivity to warm/heat is quite variable, depending on the type and dose of drug administration and on the investigating laboratory.101,105,111,129 The neurophysiological effects of chemotherapeutic treatment in animal models mimics that observed in patients. Lower doses of chemotherapeutics generate functional effects which are limited to sensory fibers, whereas higher doses also involve motor and autonomic nerves. Endpoints utilized to measure the effects of chemotherapeutics on nerve activity include: nerve conduction velocity,130–133 amplitude of action potentials,134 and changes in blood flow induced by neurostimulation.135 Investigators examining the neurophysiological effects of chemotherapy have reported a slowing of the sensory nerve conduction velocity (SNCV)130,131,136 and an increase in the action potential amplitude when examining Aδ fibers137; however, the effects on C fibers are more variable, with high-dose vincristine causing a decrease in the SNCV136 and high-dose paclitaxel causing no change in the SNCV.122 The data from skin-nerve experiments support an effect of high-dose paclitaxel to decrease the SNCV in all types of sensory neurons (Aβ, Aδ, and C fibers).134 As observed in patients receiving lower doses of chemotherapeutics, the morphological changes in the axonal diameter or myelination of the nerve bundle following lower dose treatment of animals with the various chemotherapeutics are unimpressive.12,111,116,138–140 However, lower doses of chemotherapeutics, which cause an enhanced sensitivity to nociceptive stimuli, cause a degeneration or loss of IENF, similar to that observed in patients.115,116,141–143 One advantage of using animal models is that studies can be designed to determine whether this IENF loss is a cause or an effect of changes in neuronal sensitivity following chemotherapy treatment, although, to date, these studies have not been performed. The data from the animal models suggest that both increases and decreases in neuronal sensitivity occur following treatment with chemotherapeutics, depending on the endpoint measured and the dosing paradigm administered. There is still a lack of understanding, however, as to what population of neurons is affected and the mechanisms by which these changes in sensitivity develop (Figure 1).


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Figure 1 Putative sites of chemotherapeutic toxicity in the peripheral nervous system.

5. EXPERIMENTAL STUDIES: IN VITRO MODELS OF CIPN To accurately delineate the intracellular signaling mechanisms by which chemotherapeutics alter the sensitivity of sensory neurons, investigators have broadened their research to include in vitro models of CIPN. Cultures of sensory neurons provide a tightly controlled system which allows relatively easy manipulation of protein expression and function via genetic and pharmacological tools. The limitation of neuronal cultures is that the neurons have been removed from their native environment and thus, communication with other cell types (direct or indirect), is largely altered. Furthermore, the addition of growth factors to the growth media could alter the effect of chemotherapeutics on neuronal sensitivity and outgrowth (this will be discussed below). In vitro experiments with chemotherapeutics have largely been limited to morphological studies to determine the effects of the drugs on neurite lengths in DRG cultures.130,146–151 Chemotherapyinduced toxicity, as measured by decreasing neurite length, is dependent on distal axonal exposure to the drug.148,150 For example, local application of paclitaxel or vincristine to the soma of cultured neurons does not affect the neurite length, whereas application to the distal terminals causes a shortening of the neurites. It is known that alterations of microtubule dynamics can lead to both neurite retraction and inhibition of neurite outgrowth by altering

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growth cones.152,153 The specific mechanisms underlying chemotherapyinduced decreases in IENFs are under investigation. Regardless of the specific mechanism, it is unclear whether changes in neurite length correlate with changes in the sensitivity of sensory neurons in culture and mechanistic in vitro studies to examine the effects of chemotherapeutics on the sensitivity of subpopulations of sensory neurons are limited. Several investigators have isolated the lumbar DRG from chemotherapy-treated animals to examine the effects of the drugs on electrical excitability and intracellular calcium signaling within the soma of the lumbar neurons, which predominantly innervate the hindpaws.154–156 Increases in the excitability of mediumand large-sized neurons isolated from paclitaxel-treated rats were observed: the percentage of neurons which exhibited spontaneous firing increased, while the current threshold for activation of the remaining quiescent neurons was decreased.156 The contribution of voltage-gated calcium currents to these increases in excitability were investigated by Kawakami and colleagues, who demonstrated that paclitaxel treatment, enhanced voltagedependent calcium current in both small- and medium-sized neurons.155 When neurons were isolated from paclitaxel-treated rats and examined for ATP-stimulated increases in intracellular calcium accumulation; however, a decrease in stimulated calcium levels was observed.154 It is unclear whether stimulation of intracellular calcium accumulation with a general depolarizing stimulus, such as high extracellular potassium, would elicit the same decrease in intracellular calcium. Overall, these data suggest a chemotherapy-induced increase in the excitability of sensory neurons. An effect of chemotherapeutics to modulate integrated neuronal responses, such as the stimulated release of neurotransmitters from the neurites and soma of sensory neurons, has been investigated for paclitaxel.157 Paclitaxel alters the sensitivity of isolated sensory neurons in concentration- and time-dependent manner without altering the viability of the sensory neurons. Paclitaxel can enhance or reduce TRPV1- and TRPA1-mediated release of calcitonin gene-related peptide (CGRP), depending on the magnitude and duration of exposure to the chemotherapeutic. However, paclitaxel augments CGRP release evoked by high extracellular potassium, regardless of the concentration or duration of paclitaxel exposure.149 Exposing sensory neurons in culture to cisplatin results in a concentration-dependent decrease in the TRPV1-mediated release of CGRP, even after accounting for the loss of content via cell death.158 These experiments investigate long-term effects of chemotherapeutic exposure on neuropeptide release, but some studies demonstrate a direct excitatory effect


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of chemotherapeutics on neuropeptide release at higher drug concentrations, suggesting the possibility for an acute effect of the drugs on neuronal sensitivity.159,160 To date, the different effects of the various classes of chemotherapeutics on neuropeptide release suggest that each class of drugs likely has a different mechanism of action to elicit changes in neuronal sensitivity. Using neurophysiological endpoints, such as the release of neurotransmitters from sensory neurons, which integrate the contributions of possible changes in function of ion channels, mitochondria, DNA damage, oxidative stress, and axonal transport, will be critical to determining whether all classes of chemotherapeutics alter neuronal sensitivity via the same mechanisms and identifying the specific signaling mechanisms by which neuronal sensitivity is altered by chemotherapeutics.

6. PROPOSED MECHANISMS UNDERLYING CIPN There have been multiple theories on the mechanisms by which each of the chemotherapeutics alters neuronal function. In this section, the use of pharmacological interventions that have been used for other types of neuropathic pain will be discussed. In addition, various putative mechanisms will be discussed in the context of the clinical and experimental evidence supporting or refuting that mechanism. It is appreciated that many of these proposed mechanisms may overlap, and thus, it is probable that neuronal function is altered via a combination of the proposed cellular mechanisms. Despite differences in disease pathophysiology and symptoms experienced by patients with CIPN,161 the initial approach to investigate CIPN focused on administering drugs utilized for other pain syndromes to treat the painful symptoms of peripheral neuropathy. As such, there have been many clinical studies to examine the effects of opioids,60,162 antidepressants,163–165 and antiepileptics166,167 on the symptoms of neuropathy induced by chemotherapeutics. Some of these drugs have been investigated and shown to be efficacious in reversing mechanical and/ or cold allodynia in animal models of CIPN, including opioids,168 antidepressants,169–171 and antiepileptics.172,173 Of all the aforementioned drugs, only duloxetine, a serotonin/norepinephrine reuptake inhibitor, has been demonstrated to have clinical efficacy in the treatment of chronic neuropathy symptoms induced by oxaliplatin administration.165 In fact, a recent set of guidelines published by the American Society for Clinical

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Oncologists moderately recommends duloxetine for the treatment of established CIPN, but does not endorse any other treatments for the prevention or treatment of CIPN.174

6.1 Mitochondrial dysfunction Arguably, the most investigated putative mechanism by which most chemotherapeutics are thought to alter neuronal function is via the perturbation of neuronal mitochondrial function. Changes in mitochondrial localization, altered fission, and fusion rates and changes in mitochondrial membrane permeability have all been investigated following neuronal exposure to chemotherapeutics. These alterations in mitochondria are associated with changes in calcium handling, release of cytochrome c, mitochondrial DNA damage, and enhanced production of ROS, which can all contribute to neurotoxicity. The localization of mitochondria is dependent on axonal transport via cytoskeletal components, including microtubules and actin filaments,175 and paclitaxel and cisplatin have been shown to impair the axonal movement of organelles, including mitochondria, in neurons or neuronal cells lines.176–178 Multiple different chemotherapeutics have been shown to induce mitochondrial swelling within sensory neuronal axons,116,138,179 sensory neuronal soma,180 and Schwann cells.127 Mitochondrial swelling occurs in normal neurons, but an increased incidence of swelling is associated with changes in mitochondrial function, and can be a result of mitochondrial permeability transition.181,182 Multiple chemotherapeutics have been shown to promote mitochondrial permeability transition and depolarize the mitochondria,146,183–185 theoretically resulting in a decrease in the ability of the mitochondria to respire and generate ATP for the neuron.116,117,182 Depolarization of the mitochondria also enhances the production of ROS,186 which is another putative mechanism by which chemotherapeutics alter neuronal sensitivity (see below). An alternate mechanism by which chemotherapeutics may alter mitochondrial localization and energy production is through the disruption of the balance between mitochondrial fission and fusion. Fission, the defragmentation of mitochondria, leads to a decrease in energy production and enhances the production of ROS.187 Although a change in mitochondrial fission was not observed in DRG from cisplatin-treated rats,188 paclitaxel altered mitochondrial dynamics in differentiating neuroblastoma cells.189 Because of the demonstrated effects of anticancer drugs, of multiple mechanisms, on the localization and function of mitochondria, several


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different mitoprotective drug strategies have been examined to determine whether preventing mitochondrial dysfunction might reverse the signs and symptoms of neurotoxicity. The premiere mitoprotective candidate was acetyl-L-carnitine (ALCAR). ALCAR plays a role in intermediary metabolism and is thought to be neuroprotective via an increase in fatty acid β-oxidation to subsequently increase ATP production.190 ALCAR has also been shown to reverse the depletion of plasma nerve growth factor (NGF) levels induced by cisplatin treatment.131 In preclinical experiments, ALCAR administration reversed mechanical and cold allodynia induced by paclitaxel,131,191 cisplatin,131 and bortezomib.116 ALCAR also reversed the chemotherapeutic-induced swelling and dysfunction of mitochondria.116,131,179 These preclinical data and evidence that ALCAR have therapeutic effects on neuropathy in patients with diabetes192 and HIV,193,194 prompted clinical trials to examine the effects of ALCAR on paclitaxelinduced neuropathy in patients. In a phase II study with 25 patients, the effects of ALCAR were promising, providing improvement of sensory neuropathy in 60% of patients.195 In order to confirm these hopeful findings, a prospective randomized, double-blind, placebo-controlled trial of 409 breast cancer patients receiving taxane-based adjuvant therapy were administered ALCAR. In contrast to the findings of the small-clinical trial, ALCAR treatment in the large trial increased CIPN at 24 weeks following treatment, as determined by patient self-reporting and clinician grading of sensory and motor neuropathy adverse effects.196 Another putative mitoprotective drug, olesoxime, has also been investigated to determine whether it reverses hypersensitivity in animal models of CIPN. Olesoxime binds directly to two different components of the mitochondrial membrane permeability transition pore197 to regulate depolarization of the mitochondria. In addition, treatment with olesoxime restores mitochondrial motility, compromised by treatment with paclitaxel, suggesting that olesoxime can interact with microtubule function.198 Systemic administration of olesoxime reversed mechanical allodynia in animal models of vincristine, paclitaxel, and oxaliplatin-induced CIPN,12,143,197 but did not attenuate the spontaneous activity of the peripheral C- and Aδ-fibers induced by the drugs, suggesting that the site of action for olesoxime is in the CNS.143 The translation of these protective preclinical effects of olesoxime into a clinically relevant therapeutic for CIPN has yet to be determined. A phase II clinical study (NCT00876538) to examine the effects of olesoxime on paclitaxel-induced pain and/or dysesthesia has been completed, but the study outcomes have not been released.

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Despite observations in experimental animals after anticancer drug treatment, the question of mitochondrial involvement in CIPN remains controversial. It is unclear whether mitochondrial dysfunction precedes changes in neuronal sensitivity and/or changes in neuronal morphology. Furthermore, mitochondrial changes such as those listed above have also been associated with general nerve injury199 or insult, such as that resulting from streptozotocin treatment as a preclinical model for diabetes mellitus,200 suggesting that damage to mitochondria might be a common downstream effect of nonspecific damage to sensory neurons rather than a causative mechanism by which chemotherapeutics alter nerve function.

6.2 Nitroxidative stress Chemotherapeutics have also been shown to enhance the production of both ROS and reactive nitrogen species (RNS) in sensory neurons and in the spinal cord.158,201,202 In fact, the generation of nitroxidative stress, induced by ROS and RNS, has been shown to enhance the sensitivity of nociceptive sensory neurons.203,204 Chemotherapy-induced ROS and RNS are generated by neurons, supporting satellite cells and inflammatory cells.205,206 Intracellular generators of ROS and RNS include the mitochondria, via the electron transport chain and an increased incidence of fission, and an increased activity of plasma membrane NADPH oxidase.207 Unfortunately, nitroxidative stress can compromise the survival and function of sensory neurons and supporting cells by causing DNA damage, nerve fiber demyelination, mitochondrial damage and dysfunction, activation of signal transduction pathways, and neuronal death via apoptosis.208–210 Multiple different strategies have been employed preclinically to try reverse chemotherapy-induced nociceptive behaviors with scavengers of ROS (phenyl-N-tert-butylnitrone and TEMPOL) or peroxynitrite decomposition catalysts (FeTMPyP5+ and MnTE-2-PyP5+),201,210–212 and these experiments demonstrate moderate attenuation of chemotherapy-induced hindpaw hypersensitivity to mechanical or cold stimulation. The effects of these compounds on nerve conduction velocity or IENF loss, as other indicators of peripheral neuropathy, have not yet been explored. Glutathione is another antioxidant which facilitates the reduction of the enzyme, glutathione peroxidase, to reduce lipid and hydrogen peroxides.213 N-acetylcysteine (NAC) functions to regenerate the reduced form of glutathione for continued reduction of ROS.214 In preclinical models of CIPN, exogenous administration of glutathione and NAC reduced the severity of neuropathy using nociceptive behaviors,202 sensory nerve conduction


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velocities,215,216 and neuronal morphology217 as endpoints. Following these preclinical studies, several small trials with glutathione and NAC were conducted in cancer patients receiving either cisplatin or oxaliplatin. The trials all reported a reduction in neurotoxicity, albeit the degree of protection varied greatly.218–224 In a large randomized, double-blind, placebo-controlled trial to investigate the ability of glutathione to reverse the neuropathy associated with paclitaxel/carboplatin combination treatment; however, glutathione did not prevent CIPN.225 Several small-clinical trials also demonstrated that vitamin E might have efficacy to decrease the incidence or severity of CIPN following paclitaxel or cisplatin treatment226–229; however, a phase III clinical trial failed to reproduce the beneficial effects of the putative antioxidant.230 There are some concerns about further development of antioxidant therapies to treat CIPN, since the production of ROS and RNS has been shown to be essential for the anticancer effects of chemotherapeutics.49,231

6.3 DNA damage Multiple strategies have been utilized to demonstrate the importance of DNA damage in mediating neurotoxicity induced by the platinum-derived compounds. Enhancing the activity of DNA repair enzymes, involved in either base excision or nucleotide excision repair pathways, mitigates the neurotoxicity associated with exposure to cisplatin.158,180,232 Whether enhanced repair of the nuclear or mitochondrial DNA adducts is critical for the protection against neurotoxicity is still under investigation.180 Mitochondrial DNA damage by cisplatin has been shown to induce the generation of ROS, which can be attenuated by overexpression of APE1, a DNA repair enzyme of the base excision repair pathway.158 Interestingly, carboplatin, which causes the formation of nuclear DNA adducts, but does not generate ROS or mitochondrial DNA damage,49 induces a very mild neuropathy,48,233 leading to speculation that increases in ROS generation secondary to mitochondrial DNA damage is a critical component of neuropathy induced by cisplatin and oxaliplatin.

6.4 Ion channel modulation Changes in ion channel conductance are also a putative target for chemotherapeutics to alter neuronal sensitivity. Both voltage- and ligand-gated ion channels have been shown to play a role in chemotherapy-induced changes in nociceptive behaviors. Included in these are sodium

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channels,137,234,235 calcium channels,155,173,236–238 ATP-gated channels,239 acid-sensing channels,239 and TRP channels,240–242 although much controversy persists regarding which channels mediate different modalities of chemotherapy-induced behaviors. Gabapentin, which binds to the α2δ subunit of the calcium channel,243 has been investigated in preclinical studies and found to have variable effects on nociceptive behaviors, depending on the class of chemotherapy administered. Sensitivity to gabapentin was correlated with chemotherapy-induced upregulation of the α2δ subunit of the calcium channel in the DRG and spinal cord.244,245 Both taxanes and platinum-containing agents elicit an upregulation of the α2δ subunit, and nociceptive behaviors induced by treatment with these chemotherapeutics are reversed by gabapentin administration.12,105,237,244 In contrast, vinca alkaloids do not upregulate the expression of the α2δ subunit, and nociceptive behaviors associated with vinca treatments are not reversed by gabapentin.244,245 There has been only one clinical trial to examine whether gabapentin administration reverses established CIPN in patients receiving vinca alkaloids, taxanes, or platinum-containing agents.166 The results of the trial failed to show an effect of gabapentin to reverse pain as a CIPN symptom.166 Given the dependence of gabapentin efficacy on the class of chemotherapy administered in preclinical studies, it would be interesting to determine whether gabapentin could reverse CIPN in a study with sufficient power to be able to analyze the outcomes based upon the class of chemotherapy which elicited the CIPN. Alternative strategies are being developed to target the pathophysiological function of specific ion channels without complete blockade of ion channel conductance, via the modulation of ion channelbinding proteins.246 This strategy, which is promising in the treatment of pain derived from various etiologies,247 might be a useful approach for the treatment of CIPN once the chemotherapy-induced changes in ion channels are understood. Another cause of ion channel dysfunction, specifically following treatment with oxaliplatin,235,248 is the chelation of extracellular calcium and magnesium by oxalate, a metabolic product of oxaliplatin.249 It was hypothesized that replacement of these ions, via Ca2+/Mg2+ infusions, could help to reverse acute and chronic oxaliplatin-induced neuropathy symptoms.250 Preclinical experiments demonstrated prevention of the hypersensitivity to cold,105,126 but ion replacement did not alter mechanical hypersensitivity induced by either oxaliplatin or oxalate.126 An initial retrospective review of patients receiving oxaliplatin in the absence or presence of Ca2+/Mg2+ infusions supported the theory that Ca2+/Mg2+ therapy prevented


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neuropathy, as patients receiving Ca2+/Mg2+ were administered larger cumulative doses of oxaliplatin (650 vs. 910 mg/m2 for placebo vs. Ca2+/Mg2+, respectively), and reported less acute neuropathic symptoms (laryngopharangeal dysesthesia in 9% vs. 0% of patients), and less development of grade 3 chronic neuropathy (20% vs. 8% of patients).250 Based on this retrospective data, two clinical trials were initiated to examine the efficacy of Ca2+/Mg2+ infusions to prevent oxaliplatin-induced neuropathy (CONcePT trial and N04C7). Trial progress was halted due to concerns that Ca2+/Mg2+ infusions reduced the oncolytic activity of oxaliplatin,251 however, those concerns have since been refuted.252 The data generated from the two discontinued trials were conflicting; in the CONcePT trial, Ca2+/Mg2+ infusions did prevent acute symptoms or chronic neuropathy253; whereas in the early results of the N04C7 trial,254 Ca2+/Mg2+ infusions decreased oxaliplatin-induced acute muscle spasms and the development of grade 2 or higher chronic neuropathy.254 A third trial was initiated (N08CB) to resolve whether Ca2+/Mg2+ infusions were efficacious to prevent oxaliplatin-induced neuropathy.255 An effect of infusions to prevent the development of acute or chronic oxaliplatin-induced neuropathy was not observed; however, there have been several critiques of the data interpretation from the N08CB study. Under questions are the selected choice of sensory scales used as endpoints for neuropathy and the power of the study to determine the reported negative efficacy outcomes.256,257 In light of the preclinical data, which demonstrate an effect of Ca2+/Mg2+ to reverse cold, but not mechanical, hypersensitivity, it would be useful to analyze the clinical data based on individual sensory symptoms. In this manner, information regarding whether Ca2+/Mg2+ has efficacy to prevent specific modalities of the neuropathy could be obtained.

6.5 Inflammation Another plausible mechanism by which chemotherapeutic treatments alter the sensitivity of sensory neurons is through the activation of the immune system and subsequent induction of inflammation. Several investigators have observed the activation of resident immune cells, such as the satellite cells in the DRG258 and the microglia in the dorsal horn of the spinal cord188,259 following chemotherapeutic administrations. Infiltration of macrophages in the DRG and antigen-presenting Langerhans cells in the skin has also been observed following the administration of paclitaxel.115,260 Furthermore, modulation of known inflammatory signaling pathways, such as

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NFκB141 and Toll-like receptor (TLR) signaling261,262 attenuate the behavioral effects of chemotherapy administration in preclinical models. Indeed, paclitaxel administration to rats enhances the expression of the TLR4 in the DRG and spinal cord.262 Intrathecal administration of a TLR4 antagonist, lipopolysaccharide derived from Rhodobacter sphaeroides, partially reversed the mechanical hypersensitivity associated with paclitaxel treatment.262 Several investigators have also demonstrated an upregulation of chemokine (C– C motif ) ligand 2 (CCL2 or MCP-1) following paclitaxel treatment.259,263 This increase in chemokine levels was shown to have functional importance, since intrathecal inhibition of the receptor for CCL2, the C–C chemokine receptor type 2 (CCR2), reverses mechanical allodynia, and the degeneration of IENF induced by paclitaxel administration.263 The signaling pathways by which paclitaxel upregulates CCL2 levels have not been elucidated, but CCL2 is enhanced primarily in small-diameter sensory neurons within the DRG and in astrocytes of the dorsal horn.263 The physiological function of CCL2 is to recruit and activate monocytic cell types, including macrophages and microglia. This function is apparent in the dorsal horn of the spinal cord, where a paclitaxel-induced upregulation of CCL2 activates microglia, reversible by intrathecal application of an anti-CCL2 antibody.259,263 What remains unclear, however, is how paclitaxel-induced activation of the CCL2/CCR2 pathway, which occurs in the entire dorsal column regardless of axonal length,263 can initiate neuronal sensitivity in a “stocking and glove” distribution. Further investigations into possible interactions between inflammation and axonal damage, both induced by chemotherapeutic treatment, to elicit symptoms of CIPN might uncover additional therapeutic targets to prevent or treat the neuropathy.

6.6 Neurotrophic factors An approach to reverse the symptoms of CIPN has been to ameliorate the neuropathy through the addition of neurotrophic factors in an attempt to overcome the nerve damaging effects of chemotherapeutics with growth promoting factors. The first neurotrophin to be investigated was NGF. NGF was discovered in the late 1950s as a nerve growth promoting factor and is essential for the survival of spinal sensory ganglion cells and sympathetic neurons (see review by Zhang et al. 264). NGF levels have been shown to correlate with the intensity of neuropathy symptoms induced by paclitaxel in the clinic and in the laboratory. In patients receiving paclitaxel and cisplatin therapy, treatment-induced decreases in circulating NGF levels were associated with the development of CIPN.265 Although this


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chemotherapy-induced decrease in circulating NGF levels could not be reproduced in preclinical models,110 exogenous administration of NGF with high-dose paclitaxel reversed paclitaxel-induced thermal hypoalgesia.266 In studies investigating the effects of paclitaxel and NGF on cell survival and neurite outgrowth, NGF treatment reversed neuronal degeneration, and death in embryonic DRG explants exposed to paclitaxel (1 μM) for 1–4 days.147,267 Together, these data suggest a protective effect of NGF against neurotoxicity induced by exposure to chemotherapeutics; however, NGF treatment to prevent or treat CIPN has not been tried in the clinic. One limitation to the use of NGF as a treatment for CIPN is the effect that the neurotrophin has on the sensitivity of small-diameter sensory neurons. Inflammation-induced increases in the levels of NGF have been shown to mediate the thermal and mechanical hypersensitivity associated with inflammation,268,269 thus NGF treatment may cause inflammatory-like pain in cancer patients who are already suffering from neuropathy. Indeed, antiNGF pharmacological agents have been investigated for the treatment of inflammatory pain.270 Another limiting factor in the translation of preclinical NGF effects is centered on the interpretation of the experimental data. Embryonic neurons, which were used in many of the preclinical studies, are dependent on NGF for survival.271 NGF is trafficked from the nerve terminals to the nucleus and this retrograde transport is blocked by the MTA, colchicine.272,273 Thus, the decrease in survival observed with paclitaxel exposure could be a result of possible NGF deprivation due to decreased axonal transport, rather than a positive effect of NGF to protect the neurons.274,275 Furthermore, since embryonic neurons are dependent on NGF for survival, it is difficult to interpret the survival findings, since low concentrations of paclitaxel which alter neuronal sensitivity do not commonly cause neuronal death in cultures of DRG neurons derived from adult animals.157 Other neurotrophic agents which have been investigated and have had positive results in preclinical animals include: prosaptide,129 xaliproden,276 retinoic acid,277 and recombinant human glial growth factor 2278, but so far none have demonstrated appreciable efficacy in clinical trials.279 Neurotrophic factors play an integral role not only in the survival of sensory neurons but also in the maintenance of the neurons, thus helping to establish the setpoints for neuronal sensitivity and growth.280,281 Targeting this class of compounds, without a comprehensive understanding of how chemotherapy alters intracellular signaling pathways and the axonal transport mechanisms used to traffic the products of neurotrophin signaling, is proving to be very challenging.

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6.7 Microtubule alterations An obvious mechanism by which MTAs may alter neuronal function is through the perturbation of microtubule function. Microtubules are dynamic cellular structures that have critical roles in many functions including cell signaling, mitosis and cell division, intracellular organelle and vesicular transport, cell shape and motility, and intracellular organization.32,282 The dynamic nature of microtubules, with constant growth and shortening, is necessary for microtubule physiology.283 In nondividing neurons, the MTAs have the potential to induce neurotoxicity in a very specific way by altering axonal transport along the microtubules,11,284,285 by changing the posttranslational status of microtubules,286–288 and by changing protein–protein interactions between the microtubules and cellular proteins.289–291 Bortezomib has also been shown to change microtubule dynamics and thus could mediate changes in neuronal sensitivity via a mechanism similar to the MTAs.292 Unfortunately, the anticancer efficacy of the MTAs is directly proportional to their ability to alter microtubule dynamics,293 thus modulating the microtubule interactions to prevent CIPN would most likely compromise the anticancer properties of the drugs.

7. CHALLENGES TO CIPN RESEARCH There has been very little success in translating preclinical findings to efficacious therapies for patients suffering with CIPN. One caveat that has been largely unaddressed in CIPN research is the possibility that the presence of cancer may predispose patients to neuropathy or induce novel interactions with anticancer drugs to “prime” patients to develop a more robust neuropathy than that which is observed in preclinical models. The presence of cancer alone has been shown to induce central nervous system toxicity, using deficits in cognitive dysfunction as an endpoint for patients.294 To address the possibility that the presence of cancer may also contribute to peripheral neurotoxicity, researchers are shifting their preclinical models from rats to mice.294 The mouse is well developed as a disease model for cancer research and could facilitate the necessary experiments to examine the development of neuropathy in the absence and presence of anticancer treatment in tumorburdened animals. While a possible interaction between cancer and anticancer drugs in preclinical models could underlie the paucity of translational successes from the lab to the clinic, there are other putative pitfalls that may also contribute. CIPN research was originally focused on the


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development of animal models; efforts then shifted to try to reverse evoked nociceptive behaviors induced by anticancer treatment with a variety of “pain” drugs to see if they would alleviate nociceptive behaviors in the animals. Currently, the nociceptive tests that are used to discriminate the symptoms of neuropathy and the success and/or failure of putative chemotherapy drugs in preclinical models, do not assess this modality of spontaneous pain. Indeed, this small-fiber neuropathy is proving to be very difficult to study. Research by Kalliomaki and colleagues has demonstrated that the endpoints commonly used as surrogates for neuronal sensitivity in preclinical models: thermal behaviors, axon flare reflexes, and IENF loss, do not necessarily correlate with pain levels in patients who experience pain as a symptom of the neuropathy,96 suggesting that using appropriate endpoints to monitor neuropathy, even in in vitro studies, is critical for the translational ability of the research. The neuropathy induced by chemotherapeutics is multifaceted and deriving the mechanisms for the various symptoms will take much effort. One of the distinct differences between CIPN and neuropathies induced by physical nerve damage is that the timing of the insult is defined. This predictability allows for the introduction of pharmacological agents to inhibit the neuronal effects of the chemotherapeutics. Only after, we understand the neuronal signaling pathways altered by chemotherapeutics; however, we can subsequently develop therapeutics to specifically prevent the development or maintenance of neurotoxicity without compromising the oncolytic activity of the drug.

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Peripheral neuropathy with disopyramide.

Giardiasis and peripheral neuropathy.

Peripheral neuropathy and indomethacin.

Flecainide induced peripheral neuropathy.

Propylthiouracil and peripheral neuropathy.

Symptoms: Chemotherapy-Induced Peripheral Neuropathy.

Subdural hemorrhage mimicking peripheral neuropathy.

Biotin for diabetic peripheral neuropathy.

Updates in diabetic peripheral neuropathy.

Peripheral Neuropathy Associated withHypereosinophilic Syndrome.

Peripheral neuropathy associated with fluoroquinolones.

Linezolid Induced Reversible Peripheral Neuropathy.

Peripheral neuropathy and solitary plasmacytoma.

Peripheral neuropathy for dermatologists: what if not diabetic neuropathy?

Peripheral neuropathy after chronic endoneurial ischemia.

Invited review: peripheral neuropathy in Sjogren's syndrome.

Pharmacological treatment of diabetic peripheral neuropathy.

Episodic neurological dysfunction in hereditary peripheral neuropathy.

Treatment of painful diabetic peripheral neuropathy.

Peripheral Neuropathy in Mouse Models of Diabetes.

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy.

Neuropathic pain in hereditary peripheral neuropathy.

Peripheral neuropathy after administration of tetanus toxoid.

Platelet abnormalities in diabetic peripheral neuropathy.