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. 2015 Mar 12;20(4):411–432. doi: 10.1634/theoncologist.2014-0044

Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

Abolfazl Avan a, Tjeerd J Postma b, Cecilia Ceresa c, Amir Avan a,d, Guido Cavaletti c, Elisa Giovannetti a, Godefridus J Peters a,
PMCID: PMC4391771  PMID: 25765877

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 platinum-induced neuropathy, studies on in vitro models, and appropriate trials planning to find the best patient-oriented solution.

Keywords: Neurotoxicity, Platinum, Pathogenesis, Polymorphism, Prevention, Models

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.

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 platinum-induced neuropathy, studies on in vitro models, and appropriate trials planning to find the best patient-oriented solution.

Introduction

Since the discovery of cisplatin in the mid-1960s, many platinum compounds (more than 3,000 compounds) have been developed. Thirty-five of these compounds have exhibited adequate pharmacological advantages (e.g., reaching sufficiently high plasma levels not associated with common toxicities, such as renal toxicity and thrombocytopenia) [1]. Some of them have been registered or are being considered for registration for treatment of different cancers, such as the second (carboplatin, nedaplatin, tetraplatin, and iproplatin) and third (oxaliplatin, lobaplatin, heptaplatin, satraplatin, and LA-12) generation, usually with better safety profiles [24].

Despite the efficacy of platinum analogs in cancer treatment, serious side effects, especially peripheral sensory neurotoxicity, often prevent their administration at their full efficacious doses or may considerably affect the quality of life of cancer patients being treated with them [5, 6]. Cisplatin was the first heavy metal used in several kinds of solid tumors, including lung, ovary, testis, bladder, head and neck, and endometrium [7, 8]; most patients develop a symptomatic neuropathy [9]. Second and third generations of platinum compounds have emerged in attempts to reduce the toxicity of cisplatin. Carboplatin, a second generation of platinums used to treat ovarian, non-small cell lung, and refractory testicular cancers, was thought to be associated with a lower risk of developing neurotoxicity [9]. However, the most recent Cochrane review comparing the toxicity of carboplatin versus cisplatin in combination with third-generation drugs for advanced non-small cell lung cancer reported an almost two times higher rate of neurotoxicity in the carboplatin group [10]. Oxaliplatin, as a widely used third-generation platinum analog approved for use in the treatment of metastatic colon cancer, is reported by the Food and Drug Administration to be responsible for more than 70% rate of symptomatic neurotoxicity with any severity [11] and often leads to treatment discontinuation [1214]. In other studies, approximately 80% of colorectal cancer patients treated with oxaliplatin alone or in combination with other chemotherapeutics experienced neurotoxicity [1517], and impairment may be permanent. Because the number of patients being treated with a neurotoxic agent is increasing, it is essential to understand the nature of such a problematic side effect. Furthermore, testing and validating available protective strategies in preclinical and clinical settings should be the next steps in overcoming platinum-induced peripheral neurotoxicity.

Clinical Features of Neurotoxicity

Platinum drugs are almost always given in combination with other chemotherapy drugs and/or radiation that may be neurotoxic in their own right. Early presentation of peripheral neurotoxicity can be with numbness, tingling, or paresthesia in fingers and/or toes, a decreased distal vibratory sensitivity, and/or loss of ankle jerks [5]. Moreover, prolonged treatment may also affect proprioception, which may result in ataxic gait.

Oxaliplatin and cisplatin are the two most commonly used neurotoxic platinum agents. Platinum-induced peripheral neurotoxicity can present as two clinically distinct syndromes. The acute transient paresthesia in the distal extremities, which is only commonly seen with oxaliplatin, usually occurs within the early phase of drug administration, whereas the chronic cumulative sensory neuropathy causes more persistent clinical impairments [5]. The latter deteriorates with cumulative doses [18], followed by “coasting,” wherein symptoms worsen even months after treatment withdrawal. Furthermore, patients can develop Lhermitte’s syndrome, which is a shocklike sensation of paresthesia radiating from the neck to the feet triggered by neck flexion. This phenomenon indicates the involvement of the centripetal branch of the sensory pathway within the spinal cord [19]. Neuropathy can also become irreversible. In a prospective multicenter study, Argyriou et al. [20] reported that oxaliplatin can result in an acute and chronic rate of neuropathy in 85% (169 patients of 200) and 73% (145 patients of 200) of patients, respectively.

Hearing loss or ototoxicity is another progressive and irreversible adverse effect of platinum chemotherapy [21] with a high frequency of almost 88% [22], which usually presents bilaterally and can occur during or years after treatment [23]. Nevertheless, the risk of ototoxicity may vary between cisplatin, carboplatin, and oxaliplatin treatments, and cisplatin is believed to be the most ototoxic and oxaliplatin is believed to be the least [24]. In one study, 19%–77% of patients treated with cisplatin developed bilateral sensorineural hearing loss, and 19%–42% developed permanent tinnitus [25]. Cisplatin accumulates in the cochlear tissue, forms DNA adducts, and causes inefficient and dysfunctional protein and enzyme synthesis leading to apoptosis of auditory sensory cells [26].

Diagnosis and Evaluation

The clinical diagnosis is generally not very difficult [27]. Nerve biopsies and neurophysiologic assessments are helpful for the examination of pathological and functional nerve damage (e.g., demyelinating versus axonal pathology; abnormalities in nerve conduction studies, somatosensory evoked potentials, magnetic resonance imaging, threshold tracking techniques, and quantitative sensory testing) [27]. Objective electromyography assessment of motor nerve excitability is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, which has the advantage of being widely available [28, 29]. Additionally, the threshold tracking technique is used to assess axonal excitability [30]. This technique allows the detection of sensory axonal dysfunction before clinical symptoms [18] and can be used as a predictive marker for nerve dysfunction.

Chemotherapy-induced peripheral neurotoxicity is typically a multidisciplinary medical issue, leading to different terminology, measurement, clinical evaluation, and grading, precluding the reliability of neurological assessment. However, standardization is improving. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity Scale, the FACT-Taxane scales, the Patient Neurotoxicity Questionnaire, European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire [QLQ] to assess chemotherapy-induced peripheral neuropathy, and the EORTC QLQ C30 questionnaire are scoring systems that have been used for neurotoxicity assessment to quantify the impact of chemotherapy-induced neurotoxicity on patients’ quality of life [31]. Among the questionnaires, the EORTC questionnaires are widely used nowadays [32]. Among different common toxicity criteria scales that are used for peripheral neurotoxicity assessment, the one developed by the Eastern Cooperative Oncology Group and National Cancer Institute (NCI-CTC) is most widely used [19, 3335]. Although the reliability of different assessment methods has been tested in different settings, there are vast discrepancies between patient perception and objective tools, particularly in intermediate grades [32, 36], which increase the need for a more effective and standardized method [19].

Nature of Neurotoxicity

The pathophysiology of platinum-induced peripheral neurotoxicity is not completely elucidated. Based on available data, platinum compounds may actively enter the tumor and normal cells through organic cation transporters [37], organic cation/carnitine transporters [38], and some metal transporters, such as the copper transporters [39, 40]. Platinum compounds can be excreted via platinum efflux transporters (e.g., ATP7A, ATP7B, and MRP2) [4145] (Fig. 1). The platinum adducts are formed intracellularly because of a hydrolysis process [46], resulting in interstrand cross-links, intrastrand cross-links and/or DNA-protein cross-links with platinum, affecting DNA synthesis in cancer cells [47] and mediating apoptosis [48]. Extensive DNA repair is considered as a major mechanism of chemotherapy resistance (Fig. 1), but efficient DNA repair can possibly prevent development of neurotoxicity. In dividing tumor cells, the formation of DNA adducts is supposed to cause growth inhibition and cell kills, hence eliminating the tumor cells.

Figure 1.

Figure 1.

Effects of platinated compounds (Pt) and potential mechanisms of action. Pt may enter tumor cells (Pt influx) via copper transporter, organic cation transporters, and organic cation/carnitine transporters or by passive diffusion. DNA-platinum adducts block DNA replication, transcription, and other nuclear functions and also activate signal transduction pathways, which result in apoptosis and necrosis in tumor cells. In dividing tumor cells, the formation of DNA adducts is supposed to cause growth inhibition and cell kill, hence eliminating the tumor cells. DNA damage is recognized via high mobility group nonhistone proteins (HMG1 and HMG2) and/or various DNA repair pathways, depending on the Pt analog. GSH and MTN can neutralize Pt (e.g., by a complex that can be effluxed). MRPs (multidrug resistance-associated proteins, e.g., MRP2, also known as ABCC2) and some other efflux transporters (ATP7A and ATP7B) can excrete Pt from cells (Pt efflux). The increased repair of DNA damage and protection with GSH, as well as dysregulation in apoptosis pathways and reduced Pt influx and increased Pt efflux, can induce Pt resistance.

Abbreviations: ERK, extracellular signal-regulated kinase; GSH, reduced glutathione; HMG, high mobility group nonhistone protein; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MTN, metallothionein protein; PKB (Akt), protein kinase B; Pt, platinated compounds; Sapk, stress-activated protein kinase.

Platinum products accumulate in the dorsal root ganglia (DRG), which is the main target, and in peripheral neurons (Fig. 2). Because these cells are postmitotic and not dividing, the formation of DNA adducts is not lethal, although the extent of DNA cross-links in DRG neurons at a specific cumulative dose strongly correlates with the degree of neurotoxicity [49]. Cisplatin produces approximately three times more adducts in the DRG compared with oxaliplatin [50], which is consistent with its higher neurotoxicity [12]. Platinum adducts probably cause axonal changes secondary to the neuronal damage [51], whereas brain and spinal cord are to some extent protected by the blood-brain barrier (BBB) [52]. However, there are data showing that cisplatin crosses the BBB and can accumulate when repeated dosages are given [53]. This can cause demyelination and vacuolar changes in the white matter [54]. It is believed that impaired axonal voltage-gated sodium channels kinetics can interfere with channel kinetics by oxalate (a metabolic product of oxaliplatin) [55] and can also reduce sodium ions current [56]. Sittl et al. [57] also showed that cooling in the presence of oxaliplatin induced bursts of action potentials in myelinated A but not unmyelinated C-fibers from human and mouse peripheral axons. Consequently, these alterations led to enhanced resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons. Potassium channel blockade and calcium chelation are also two other etiologic possibilities [56, 5860]. Besides, oxidative stress and mitochondrial dysfunction are regarded as another probable etiology of the apoptosis [61]. Podratz et al. [62] showed that cisplatin might inhibit mitochondrial DNA replication and cause mitochondrial vacuolization and degradation in DRG neurons in vitro and in vivo. These events can, to some extent, explain the mechanism of the neurotoxic effect of platinum compounds.

Figure 2.

Figure 2.

Mechanism of acute and chronic platinum-induced neurotoxicity. Oxaliplatin may impair normal calcium-sensitive voltage-gated sodium channels, which cause acute neurotoxicity. Platinated compound (Pt) adducts can accumulate in dorsal root ganglia and lead to chronic neurotoxicity. Because these cells are postmitotic and not dividing, the formation of DNA adducts is not lethal to neurons. Increased Pt influx by organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs), as well as polymorphisms and/or overexpression of some genes that play a role in Pt metabolism (e.g., in OCT, OCTN, and GSH), can contribute to Pt-induced neurotoxicity.

Abbreviations: GSH, reduced glutathione; Pt, platinated compounds; VG, voltage-gated.

Pharmacogenetics

Single-nucleotide polymorphisms (SNPs) may play a key role in determining the induction of neurotoxicity, as well as apoptosis, because they may impair DNA repair pathways, including genes in base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair pathways [63] (Fig. 2). Moreover, SNPs can alter the drug metabolism, cell cycle control, detoxification, or excretion pathways, which finally may lead to drug toxicities, e.g., neurotoxicity. Several studies evaluated the pharmacogenetic association of SNPs with potential functional changes in the encoded protein that play a role in drug disposition, metabolism, and detoxification, DNA repair, and cancer-cell resistance and that may lead to platinum peripheral neurotoxicity [19]. However, the results are scattered and diverse with several methodological flaws, including small sample size, retrospective study design, and the implementation of a post hoc analysis of oncology-based databases of different, not preplanned sizes as well as lacking a prestudy hypothesis based on the known role of the investigated targets in the peripheral nervous system and the inappropriate outcome measures for neurological impairment [64] (Table 1).

Table 1.

Studies on the genes with or without significant correlations with incidence and/or severity of platinum-induced peripheral neurotoxicity

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There are controversial reports on the association of polymorphisms in some genes with platinum-induced neurotoxicity. These genes include ATP-binding cassette subfamily B member 1 (ABCB1) [6568], ATP-binding cassette subfamily C member 1 or 2 (ABCC1, C2, or CG2) [69, 70], alanine-glyoxylate aminotransferase (AGXT) [69, 72, 73, 77, 94], cyclin H (CCNH) [70], catechol O-methyltransferase (COMT) [76], cytochrome P450s (CYPs; e.g., CYP2C8, CYP3A5 exons 3 and 5) [6568], excision repair cross-complementation group 1 (ERCC1) and ERCC2 (alias XPD, xeroderma pigmentosum group D) [67, 68, 71, 74, 75, 7787, 88], integrin β3 (ITGB3) [92], glutathione S-transferases (e.g., GSTM1 [69, 77, 78, 85, 86, 88, 8991], GSTM3 [84, 75], and GSTT1 [88, 91]), voltage-gated sodium channel genes (SCNAs) [20, 71, 98], thiopurine S-methyltransferase (TPMT) [76], and x-ray repair cross-complementing protein 1 (XRCC1) [71, 73]. Although some data support the role of the mentioned genetic variations in the presentation and severity of platinum-induced peripheral neurotoxicity, the results are scattered and diverse (Tables 1, 2), which may form leads for future research.

Table 2.

Polymorphisms associated with platinum-induced peripheral neuropathy

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ABCB1, ABCC1, ABCC2, ABCG2, and probably several other subfamily members mediate the cellular trafficking of drugs, their metabolites, and their endogenous factors, e.g., platinum efflux [99, 100]. CCNH plays an important role in the cell cycle progression, the transcriptional activity of the RNA polymerase II, and the DNA repairing process [101]. Thus, it may deregulate the repair after platinum damage to the dorsal root ganglia neurons [102]. COMT and TPMT, which encode enzymes that metabolize catecholamine-containing chemical and thiopurine drugs via methylation [103], respectively, might be associated with cisplatin-related hearing loss [104, 105].

Glutathione S-transferases (GSTs), a family of enzymes that have an important role in detoxification, have been extensively studied for the relation of SNPs with neurotoxicity induced by platinated compounds. GSTs are involved in detoxification through glutathione conjugation of electrophilic compounds (e.g., GSTM1 and GSTM3). A GSTP1 SNP (rs16953), for example, has been investigated in relation to peripheral neurotoxicity of platinum compounds in 24 studies (Table 1). Among these, 9 studies reported an association of this SNP with the course and severity of peripheral neurotoxicity [68, 74, 77, 80, 85, 8890, 93], whereas other researchers reported contradicting results in 15 studies with regard to the association of GSTP1 gene variants with neurotoxicity [67, 71, 72, 75, 78, 81, 83, 84, 86, 87, 91, 9497]. Moreover, recent meta-analysis showed no significant associations between GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy in a dominant model (odds ratio [OR] = 1.08, 95% confidence interval [CI] 0.67–1.74, p = .754), a recessive model (OR = 1.67, 95% CI 0.56–4.93, p = .357), and allelic analysis (OR = 1.22, 95% CI 0.67–2.24, p = .513) [106]. This inconsistency between the findings might be explained by the difference in the cancer type, ethnicity of the population studied, and/or number of the patients enrolled in each study [19].

Other studies evaluated the association of platinum-induced peripheral neurotoxicity with different SNPs in ERCC1 [67, 68, 77, 71, 74, 7887], ERCC2 [71, 88], and XRCC1 [71, 73], which are parts of the nucleotide excision repair (ERCC1 and ERCC2) and base excision repair (XRCC1) pathways and are required for repair of DNA lesions [107]. Although Lee et al. [73] reported the polymorphism Arg399Gln (rs25487) in XRCC1 associated with less grade 2–4 sensory neuropathy in Korean patients treated with oxaliplatin-based treatment, the recent meta-analysis found it to be generally associated with poor clinical outcomes [108]. AGXT prevents accumulation of glyoxylate in the cytosol by converting it into glycolate, which is subsequently metabolized by lactate dehydrogenase into oxalate, the metabolite of oxaliplatin [109]. Pharmacogenetic analyses evaluated also cytochrome P450s [6568], which are major enzymes of drug metabolism and bioactivation (e.g., CYP2C8 and CYP3A5), and ITGB3 [92], which belongs to the large family of integrins, known to participate in cell adhesion and cell surface-mediated signaling.

A recent study has provided evidence that SNPs in voltage-gated sodium channel genes (SCNAs; e.g., SCN4A-rs2302237 and SCN10A-rs1263292) can play a causal role in oxaliplatin-based peripheral neurotoxicity [20, 57] (Table 1). A polymorphism in SCN1A (rs3812718) was also reported to be associated with decreased neurotoxicity [85]. However, these results still need to be validated by appropriate larger and prospective studies. Won et al. [71], in a genome-wide pharmacogenomic approach, identified nine novel polymorphisms associated with and predictors of severe oxaliplatin-induced peripheral neurotoxicity, including rs10486003 (tachykinin, precursor 1 [TAC1]), rs2338 (forkhead box C1 [FOXC1]), rs830884 (integrin α1 [ITGA1]), rs843748 (acylphosphatase 2, muscle type [ACYP2]), rs4936453 (B-cell translocation gene 4 [BTG4]), rs17140129 and rs6924717 (phenylalanyl-tRNA synthetase 2 [FARS2]), rs12023000 (calcium/calmodulin-dependent protein kinase II inhibitor 1 [CAMK2N1]), and rs797519 (deleted in lymphocytic leukemia, 7 [DLEU7]) [71]. These genes may account for the mechanism of neurotoxicity prevention by calcium-magnesium infusions or may be associated with the important oxalate and glyoxylate outcome pathway [72]. However, none of the SNPs in the discovery samples (96 patients with colon cancer) surpassed genome-wide significance, and these SNPs were not significant in their validation set (247 patients with colorectal cancer; p = .05–.19) [71]. However, the authors noted that this limitation might be overcome by increasing the sample size in a prospective analysis.

Some evidence demonstrated that mitogen-activated protein kinase pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (Sapk), and p38, might also have a causal effect on chemotherapy-induced peripheral neuropathies [110]. Normally, there is a balance between ERK1/2 and p38 activation, which regulates neuronal apoptosis, and JNK/Sapk, which preserves neuronal degeneration. This balance is also altered by platinum derivatives [109].

Neuroprotection

Neuroprotective Agents, Mechanisms, and Controversies

Several model systems have been used to study the nature of overall neurotoxicity and the effect of potential neuroprotective drugs. These include overall neurotoxicity signs in the animal, specific models including the DRG of rats [111113], the structure of the cerebral ganglia of snails [114116], in vitro models such as neurite extension [117121], and evaluation of biomarkers of neurotoxicity such as cyclin B [122]. These models have been very useful to select proper potential neuroprotective drugs to be evaluated in the clinic. Unfortunately, preventive and therapeutic treatment options are not sufficient so far to bypass neurotoxicity [9, 19, 123]. However, a few drugs can, to some extent, protect against platinum-induced peripheral neurotoxicity (Table 3). Neuroprotective drugs include the following.

Table 3.

Randomized controlled trials on neuroprotective agents for the prevention of platinum-induced peripheral neurotoxicity

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Detoxicants

Sodium thiosulfate (STS) is a reactive thiol agent used clinically as an antidote to cyanide or nitroprusside poisoning, and at high molar excess, it binds to and inactivates the electrophilic platinum compound. Its use includes otoprotection [169173] (discussed separately under “Neuro- Versus Chemoprotection”).

Amifostine is an organic thiophosphate also regarded as a cytoprotective and detoxicant agent [117]. There are successful in vitro results supporting amifostine neuroprotection against cisplatin [120], as well as against oxaliplatin [122]. Some clinical data, with different levels of reliability (Table 3), indicated that amifostine exerts some protection against peripheral neurotoxicity of carboplatin plus paclitaxel combination therapy [127129, 131], oxaliplatin [126], and cisplatin [133, 134], whereas two other studies have failed to show significant neuroprotection against carboplatin plus paclitaxel combination therapy [130] and cisplatin [132] (Table 3). BNP7787 (Dimesna, Tavocept, 2,2′-dithio-bis-ethanesulfonate) has also shown some cytoprotective activities in vitro [174]. This effect was not confirmed in the clinical setting, although the study was unblinded with no placebo-controlled group and high risk of bias [135].

NGF Stimulants

Circulating nerve growth factor (NGF) levels are reduced in cancer patients with neuropathy caused by neurotoxic agents [175]. In addition, Schmidt et al. [176] showed in a mouse model that NGF exerted a major effect on the metabolism of transmitters associated with nociception, pain, and sensation in cervical dorsal root ganglia in various models of neurotoxicity, including the cisplatin-induced neuropathy. Thus, NGF in high doses may protect DRG neurons exposed to cisplatin [176], as well as against oxaliplatin-induced peripheral neurotoxicity [177]. They hypothesized that this effect could be due to NGF’s ability to preserve the correct neuronal differentiation status by blocking the cell cycle in the G0 phase.

The synthesis of NGF can be stimulated by Org 2766 [34, 156, 159], leukemia inhibitory factor (rhuLIF) [162], retinoic acid [161, 178], glutamine [144], and acetyl-l-carnitine [179181]. The two latter may also increase glutathione production [182, 183]. Two clinical trials [158, 159] with relatively small sample sizes showed some degree of Org 2766 neuroprotection in patients with peripheral neurotoxicity induced by cisplatin, whereas two other studies could not find a significant decrease in the incidence and severity of neuropathy [156, 157] (Table 3). Furthermore, derivatives of erythropoietin, a protein signaling cytokine, (e.g., carbamylated erythropoietin and asialo-erythropoietin) have been successful in vitro and in animal models [184, 185].

Retinoic acid (all-trans-retinoic acid) is a stimulator of NGF and the expression of its receptor, activator of retinoid acid receptors with neuroprotective profile [177]. It is also a prodifferentiating agent that counteracts platinum-induced neuronal apoptosis through activating both JNK/Sapk and ERK1/2 [177]. Additionally, Arrieta et al. [186] reported a decrease in incidence and severity of neuropathy induced by cisplatinpaclitaxel combination when retinoic acid was administered.

Antioxidants or Antioxidant-Related Agents

α-Lipoic acid, a physiologic antioxidant with some neuroprotective activity [187], has recently been tested in a well-designed clinical trial [125] in which no significant decrease in incidence and severity of peripheral neurotoxicity induced by cisplatin and oxaliplatin has been reported (Table 3). α-Tocopherol (vitamin E), as another antioxidant, acts against free radicals. Four trials have evaluated the effect of vitamin E in preventing platinum, mainly cisplatin-induced peripheral neurotoxicity, and showed significantly lower incidence and severity of neuropathy in the vitamin E group compared with the control group [164167], although all were with high risk of bias and low strength of evidence (Table 3).

Reduced glutathione is a natural neuroprotectant antioxidant derived from the γ-glutamyl transpeptidase with a high affinity for heavy metals, which may prevent the accumulation of platinum in the DRG [146, 147, 149, 150]. Additionally, it is a natural free-radical scavenger and can also stimulate NGF receptors [188]. Five different clinical trials demonstrated the potential of glutathione in reducing the incidence and severity of neuropathy induced by oxaliplatin [146, 147] or cisplatin [149, 150, 152], whereas three others could not find significant neuroprotective effect against carboplatin (carboplatin-paclitaxel combination) [145] or cisplatin-induced peripheral neurotoxicity [148, 151] (Table 3). Similarly, oral glutamine, another derivative of the γ-glutamyl transpeptidase, may reduce the incidence and severity of oxaliplatin-induced peripheral neuropathy [144], although based on a randomized, but neither blinded nor placebo-controlled trial.

N-Acetylcysteine is a glutathione precursor that is believed to increase the blood concentration of glutathione [124]. The only available clinical trial on N-acetylcysteine in a small population revealed some potential neuroprotective effects against oxaliplatin-induced peripheral neurotoxicity [124] (Table 3). d-Methionine, a sulfur-containing nucleophilic antioxidant, has also shown successful neuroprotection against cisplatin-induced neurotoxicity in cortical network in vitro [189].

Electrolytes, Chelators, and Ion Channel Modulators

The electrolytes calcium and magnesium may act as chelators against oxalate accumulation and will probably protect the voltage-gated sodium channels from alteration [140]. Among six available randomized clinical trials conducted to evaluate the efficacy of calcium/magnesium infusion against oxaliplatin-induced peripheral neurotoxicity (Table 3), two preliminary studies were unsuccessful in showing any protection by intravenous calcium/magnesium [140, 141]. Knijn et al. [139], in a retrospective analysis study on patients with oxaliplatin-induced peripheral neurotoxicity, could only find reduced rate of grade 1 peripheral neurotoxicity, considering the high risk of bias. Later, two clinical studies have shown some levels of neuroprotection against the development of oxaliplatin-induced neuropathy [138]. However, the two most recent trials did not confirm the neuroprotective role of calcium/magnesium against oxaliplatin-induced neuropathy [137, 136]. Moreover, Han et al. [136] have shown that calcium and magnesium infusions do not alter the pharmacokinetics of either intact oxaliplatin or free platinum, whereas there was no evidence of a pharmacokinetic interaction between calcium/magnesium and oxaliplatin, meaning that these infusions may provide no benefit in reducing acute oxaliplatin-induced peripheral neurotoxicity.

Carbamazepine and oxcarbazepine are known as antiseizure drugs. They block voltage-sensitive sodium channels and some calcium channels, which might protect the voltage-gated sodium channels from alteration by oxalate [55, 190]. These two agents have also been tested in clinical trials with relatively small sample sizes, with one showing neutral effect [142] and the other suggesting benefit, although with an unblinded control arm [160] (Table 3).

Nimodipine is a calcium channel blocker that did not show significant neuroprotection against cisplatin in the only clinical trial ever done [155]. Although the trial had to be terminated because of severe gastrointestinal toxicity, the results by that time did not support neuroprotection. A multicenter trial on diethyldithiocarbamate, a chelating agent and antioxidant that prevents the degradation of extracellular matrix as an initial step in cancer metastasis and angiogenesis, did not demonstrate a significant chemoprotective effect against cisplatin-induced neurotoxicity [143] (Table 3).

Other Compounds

There are also some data supporting the preventive effect of other agents against platinum-induced peripheral neurotoxicity. Acetyl-l-carnitine is a natural compound that plays a role in intermediary metabolism and has an antioxidant activity [191]. In vitro data support its effectiveness for platinum-induced neurotoxicity [179], but a recent randomized double-blinded placebo-controlled trial discouraged its administration for a nonplatinum agent [192]. Xaliproden is a 5-hydroxytryptamine (HT)1A agonist that also acts as a neuromodulator with neurotrophic and neuroprotective effects in vitro [193] and had positive results in a clinical setting as well [168], although the results have yet to be published. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor that also modulates the oxidative stress in the nervous system and may block sodium channels, which showed some neuroprotective effect in a small clinical trial [163].

Goshajinkigan (Kampo medicine), composed of 10 natural ingredients, is frequently used for alleviating symptoms of diabetic peripheral neuropathy in Japan; it is shown to have some neuroprotective potentials [194, 195]. Moreover, its safety and efficacy for preventing oxaliplatin-induced peripheral neurotoxicity have been tested in two clinical trials [153, 154] (Table 3). Nishioka et al. [154] reported a significantly lower incidence of grade 3 peripheral neurotoxicity, although based on a small sample size with unblinded control group. The findings of a phase II, multicenter, randomized, double-blind, placebo-controlled trial by Kono et al. [153] were also suggestive of reduced but insignificant rate of peripheral neurotoxicity grade 2 and 3 in patients treated with oxaliplatin compared with placebo (incidence of grade 2 neuropathy until the eighth cycle: 39% and 51% in the Kampo and placebo groups, respectively [relative risk, 0.76; 95% CI 0.47–1.21]; and grade 3: 7% vs. 13% [0.51, 0.14–1.92]).

Nondrug Approach

There are other modalities that might enhance the effectiveness of the treatment while diminishing side effects or prevent peripheral neurotoxicity. It might be helpful to identify risk factors for neurotoxicity, such as pre-existing neuropathy, inherited neuropathies, age-related axonal loss, diabetes mellitus, alcohol abuse, and poor nutritional status, that may predispose to more severe symptoms from platinum-induced peripheral neurotoxicity [196].

Timing in drug administration to account for biological rhythms (chronotherapy) seems also very important [197], because there are drugs and disease conditions, including cancers suggestive of an optimal circadian time of drug administration [198]. However, in a meta-analysis on five randomized controlled trials with 958 patients, there was no significant difference in the incidence of peripheral sensory neuropathy after chronomodulation [199].

Finally, regarding the paucity of evidence about preventive and therapeutic strategies, treatment modification and drug withdrawal remain the most effective modalities for majority of patients [31], which indeed necessitates more adequately powered preclinical and clinical researches to find better alternative modalities [200, 201].

Neuro- Versus Chemoprotection

It is essential to demonstrate whether the application of a neuroprotective agent might diminish the efficacy of the therapeutic agent. However, this potential adverse effect has been tested with different agents. As an example, cisplatin and carboplatin are used in induction and myeloablative chemotherapy for high-risk neuroblastoma, but because of significant ototoxicity in children, their administration may be compromised. Harned et al. [169] showed that the exposure of six neuroblastoma cell lines to STS, at 6 hours after cisplatin, did not bind to and eliminate the circulating cytotoxic compound and thus did not affect the antitumor effect of the platinum agent, even under hypoxic conditions. However, a significant undesired protection against cisplatin cytotoxicity was seen when the neuroblastoma cells were simultaneously exposed to both cisplatin and STS combinations. Moreover, Harned et al. [169] demonstrated that in a subcutaneous neuroblastoma xenograft model in nu/nu mice, mice receiving cisplatin alone or cisplatin plus STS after 6 hours had significantly better progression-free survival rates (p < .03) compared with controls or mice treated with concurrent cisplatin and STS administration. Likewise, Muldoon et al. [170] reported that delaying the administration of STS for 6–8 hours after carboplatin did not reduce its antitumor activity in a human small cell lung cancer xenograft model in the rat, but still protected against ototoxicity in guinea pigs. Moreover, Dickey et al. [171] found that adding STS simultaneously or up to 2 hours postcisplatin protected against the antitumor effect of cisplatin in glioblastoma, SKOV3 ovarian carcinoma, medulloblastoma, and small cell lung cancer cell lines, but that delayed STS administration for 6 hours did not show a significant chemoprotection in any of the cell types.

The use of STS to prevent hearing loss in children with a variety of malignancies has been tested in two phase III randomized trials SIOPEL6 (NCT00652132) [172] and COG ACCL0431 (NCT00716976) [173]. In the preliminary report of COG, presented at the 2014 annual American Society of Clinical Oncology (ASCO) meeting [173], a protective effect of STS was found in reducing the proportion of hearing loss compared with observation (29% versus 55%; p = .006). In this trial, 126 cancer patients were randomized to either cisplatin infusions alone or, to prevent cisplatin-induced hearing loss, combined with STS at 16 g/m2 IV over 15 minutes beginning 6 hours after the completion of each cisplatin dose. The median postdiagnosis follow-up was 2.1 years. However, the potentially lower survival seen in the patients with disseminated disease receiving STS (event-free survival 60% versus 70%, p = .53; overall survival 75% versus 89%, p = .50) raises some concern of a tumor-protective effect of STS.

Treatment

The efficacy of some antidepressants, anticonvulsants, and a topical gel has been tested in six trials for treatment of platinum-induced peripheral neurotoxicity. Smith et al. [202] studied the effect of duloxetine in a randomized, placebo-controlled, crossover trial of 231 patients with either platinum or taxane neurotoxicity. Patients received 30 mg of duloxetine for the first week and 60 mg of daily duloxetine for 4 more weeks. Duloxetine significantly reduced pain and paresthesia, especially in oxaliplatin group. In contrast, 50 mg of daily amitriptyline or 100 mg of nortriptyline, in two separate trials, failed to demonstrate any significant improvements in patient-reported sensory symptoms, as well as objective scorings [203]. Similarly, trials testing gabapentin at a target dose of 2,700 mg/day [204] or lamotrigine at a target dose of 300 mg/day [205] failed to demonstrate any benefit for treatment of peripheral neurotoxicity. Finally, one trial evaluated a compounded topical gel containing baclofen (10 mg), amitriptyline HCl (40 mg), and ketamine (20 mg) on 208 randomly allocated patients [206], and a significant improvement in motor subscale scores was observed.

Future

There are some promising results favoring the ability of some neuroprotective agents to reduce the rate of subsequent neurotoxicity induced by platinum analogs. However, the most recent update of the Cochrane review on chemo-neuroprotective agents found insufficient data to conclude that any of the available chemoprotective agents is sufficiently effective in preventing or limiting the neurotoxicity of platinum drugs. Albers et al. [9] reviewed 29 randomized controlled trials (RCTs) or quasi-RCTs, in which 2,906 participants received chemotherapy with cisplatin or related compounds. Patients were also evaluated for quantitative sensory testing (primary outcome) or other measures including nerve conduction or neurological impairment rating using validated scales (secondary outcomes) before and 6 months after completing chemotherapy (Table 3). Likewise, the most recent ASCO Clinical Practice Guideline [123] based on a systematic review on 48 RCTs, including 35 RCTs on platinum-induced peripheral sensory neurotoxicity, did not recommend any established agent for the prevention of platinum-induced peripheral neurotoxicity. Only for the treatment of existing oxaliplatin neuropathy, they advised duloxetine, for which intermediate strength of evidence is present, considering the balance between benefit and harm [123].

Altogether, no neuroprotective strategy can yet be recommended for prevention and treatment of platinum-induced neurotoxicity, with a possible exception for duloxetine for oxaliplatin. There is a genetic diversity between patients, leading to differences in drug response including the side effects; hence a neuropathy preventive strategy should be individualized for each patient.

A pharmacogenetic approach might be useful in understanding the cause of peripheral neurotoxicity and tailoring the most suitable chemotherapy for each patient. A genome-wide pharmacogenomic approach may also be useful in identifying novel polymorphism predictors of severe platinum-induced peripheral neurotoxicity that may be used in personalized chemotherapy [71]. However, it is highly recommended that the positive and negative effects of the antineoplastic agents be studied in detail in preclinical settings before implementation in clinical practice. In particular, the central nervous system of animals can be used to quantify the effects of platinated compounds on neurons that corroborate clinical data and suggest them as suitable models for studying possible neurotoxicity of platinum agents [111121]. Some in vitro models can also be used to investigate morphological parameters affected by platinum compounds [122]. These models enable measuring the effect of the drugs on neurons along with testing the neurogenic potential of neuroprotective compounds.

Conclusion

Our knowledge about the pathophysiology of platinum-induced peripheral neurotoxicity and suggested neuroprotective strategies is diverse and not adequately powered. Therefore, a thorough investigation of available evidence is important to design new, solid studies to tailor appropriate treatment to individual patients. This will minimize the burden of peripheral neurotoxicity, optimizing the potentially positive impact of the chemotherapeutic medication.

This article is available for continuing medical education credit at CME.TheOncologist.com.

Acknowledgment

This work was partially supported by a grant from Cancer Center Amsterdam Foundation 2012 (to Elisa Giovannetti, Amir Avan, and Godefridus J. Peters).

Author Contributions

Conception/Design: Abolfazl Avan, Tjeerd J. Postma, Godefridus J. Peters

Provision of study material or patients: Abolfazl Avan, Godefridus J. Peters

Collection and/or assembly of data: Abolfazl Avan

Data analysis and interpretation: Abolfazl Avan, Tjeerd J. Postma, Guido Cavaletti, Elisa Giovannetti

Manuscript writing: Abolfazl Avan, Tjeerd J. Postma, Cecilia Ceresa, Amir Avan, Guido Cavaletti, Elisa Giovannetti, Godefridus J. Peters

Final approval of manuscript: Abolfazl Avan, Tjeerd J. Postma, Guido Cavaletti, Elisa Giovannetti, Godefridus J. Peters

Disclosures

The authors indicated no financial relationships.

References

  • 1.Fuertes MA, Castilla J, Alonso C, et al. Novel concepts in the development of platinum antitumor drugs. Curr Med Chem Anticancer Agents. 2002;2:539–551. doi: 10.2174/1568011023353958. [DOI] [PubMed] [Google Scholar]
  • 2.Boulikas T, Pantos A, Bellis E, et al. Designing platinum compounds in cancer: Structures and mechanisms. Cancer Ther. 2007;5:537–583. [Google Scholar]
  • 3.Pichler V, Mayr J, Heffeter P, et al. Maleimide-functionalised platinum(IV) complexes as a synthetic platform for targeted drug delivery. Chem Commun (Camb) 2013;49:2249–2251. doi: 10.1039/c3cc39258a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Ali I, Wani WA, Saleem K, et al. Platinum compounds: A hope for future cancer chemotherapy. Anticancer Agents Med Chem. 2013;13:296–306. doi: 10.2174/1871520611313020016. [DOI] [PubMed] [Google Scholar]
  • 5.Argyriou AA, Bruna J, Marmiroli P, et al. Chemotherapy-induced peripheral neurotoxicity (CIPN): An update. Crit Rev Oncol Hematol. 2012;82:51–77. doi: 10.1016/j.critrevonc.2011.04.012. [DOI] [PubMed] [Google Scholar]
  • 6.Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): What we need and what we know. J Peripher Nerv Syst. 2014;19:66–76. doi: 10.1111/jns5.12073. [DOI] [PubMed] [Google Scholar]
  • 7.Mollman JE. Cisplatin neurotoxicity. N Engl J Med. 1990;322:126–127. doi: 10.1056/NEJM199001113220210. [DOI] [PubMed] [Google Scholar]
  • 8.Prestayko AW, D’Aoust JC, Issell BF, et al. Cisplatin (cis-diamminedichloroplatinum II) Cancer Treat Rev. 1979;6:17–39. doi: 10.1016/s0305-7372(79)80057-2. [DOI] [PubMed] [Google Scholar]
  • 9.Albers JW, Chaudhry V, Cavaletti G, et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;3:CD005228. doi: 10.1002/14651858.CD005228.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.de Castria TB, da Silva EM, Gois AF, et al. Cisplatin versus carboplatin in combination with third-generation drugs for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2013;8:CD009256. doi: 10.1002/14651858.CD009256.pub2. [DOI] [PubMed] [Google Scholar]
  • 11.Ibrahim A, Hirschfeld S, Cohen MH, et al. FDA drug approval summaries: Oxaliplatin. The Oncologist. 2004;9:8–12. doi: 10.1634/theoncologist.9-1-8. [DOI] [PubMed] [Google Scholar]
  • 12.McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther. 2009;8:10–16. doi: 10.1158/1535-7163.MCT-08-0840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Grothey A. Oxaliplatin-safety profile: Neurotoxicity. Semin Oncol. 2003;30(suppl 15):5–13. doi: 10.1016/s0093-7754(03)00399-3. [DOI] [PubMed] [Google Scholar]
  • 14.Grothey A, Goldberg RM. A review of oxaliplatin and its clinical use in colorectal cancer. Expert Opin Pharmacother. 2004;5:2159–2170. doi: 10.1517/14656566.5.10.2159. [DOI] [PubMed] [Google Scholar]
  • 15.Argyriou AA, Briani C, Cavaletti G, et al. Advanced age and liability to oxaliplatin-induced peripheral neuropathy: Post hoc analysis of a prospective study. Eur J Neurol. 2013;20:788–794. doi: 10.1111/ene.12061. [DOI] [PubMed] [Google Scholar]
  • 16.Argyriou AA, Cavaletti G, Briani C, et al. Clinical pattern and associations of oxaliplatin acute neurotoxicity: A prospective study in 170 patients with colorectal cancer. Cancer. 2013;119:438–444. doi: 10.1002/cncr.27732. [DOI] [PubMed] [Google Scholar]
  • 17.Argyriou AA, Velasco R, Briani C, et al. Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): A prospective evaluation of 150 colorectal cancer patients. Ann Oncol. 2012;23:3116–3122. doi: 10.1093/annonc/mds208. [DOI] [PubMed] [Google Scholar]
  • 18.Park SB, Lin CS, Krishnan AV, et al. Oxaliplatin-induced neurotoxicity: Changes in axonal excitability precede development of neuropathy. Brain. 2009;132:2712–2723. doi: 10.1093/brain/awp219. [DOI] [PubMed] [Google Scholar]
  • 19.Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 2011;12:1151–1161. doi: 10.1016/S1470-2045(11)70131-0. [DOI] [PubMed] [Google Scholar]
  • 20.Argyriou AA, Cavaletti G, Antonacopoulou A, et al. Voltage-gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin-induced peripheral neurotoxicity: Results from a prospective multicenter study. Cancer. 2013;119:3570–3577. doi: 10.1002/cncr.28234. [DOI] [PubMed] [Google Scholar]
  • 21.van As JW, van den Berg H, van Dalen EC. Medical interventions for the prevention of platinum-induced hearing loss in children with cancer. Cochrane Database Syst Rev. 2014;7:CD009219. doi: 10.1002/14651858.CD009219.pub3. [DOI] [PubMed] [Google Scholar]
  • 22.McHaney VA, Thibadoux G, Hayes FA, et al. Hearing loss in children receiving cisplatin chemotherapy. J Pediatr. 1983;102:314–317. doi: 10.1016/s0022-3476(83)80551-4. [DOI] [PubMed] [Google Scholar]
  • 23.Bertolini P, Lassalle M, Mercier G, et al. Platinum compound-related ototoxicity in children: Long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol. 2004;26:649–655. doi: 10.1097/01.mph.0000141348.62532.73. [DOI] [PubMed] [Google Scholar]
  • 24.McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Saf. 1995;13:228–244. doi: 10.2165/00002018-199513040-00003. [DOI] [PubMed] [Google Scholar]
  • 25.Brydøy M, Oldenburg J, Klepp O, et al. Observational study of prevalence of long-term Raynaud-like phenomena and neurological side effects in testicular cancer survivors. J Natl Cancer Inst. 2009;101:1682–1695. doi: 10.1093/jnci/djp413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Thomas JP, Lautermann J, Liedert B, et al. High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity. Mol Pharmacol. 2006;70:23–29. doi: 10.1124/mol.106.022244. [DOI] [PubMed] [Google Scholar]
  • 27.Verstappen CC, Heimans JJ, Hoekman K, et al. Neurotoxic complications of chemotherapy in patients with cancer: Clinical signs and optimal management. Drugs. 2003;63:1549–1563. doi: 10.2165/00003495-200363150-00003. [DOI] [PubMed] [Google Scholar]
  • 28.Hill A, Bergin P, Hanning F, et al. Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability. BMC Cancer. 2010;10:451. doi: 10.1186/1471-2407-10-451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Wilson RH, Lehky T, Thomas RR, et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol. 2002;20:1767–1774. doi: 10.1200/JCO.2002.07.056. [DOI] [PubMed] [Google Scholar]
  • 30.Krishnan AV, Goldstein D, Friedlander M, et al. Oxaliplatin and axonal Na+ channel function in vivo. Clin Cancer Res. 2006;12:4481–4484. doi: 10.1158/1078-0432.CCR-06-0694. [DOI] [PubMed] [Google Scholar]
  • 31.Cavaletti G, Alberti P, Frigeni B, et al. Chemotherapy-induced neuropathy. Curr Treat Options Neurol. 2011;13:180–190. doi: 10.1007/s11940-010-0108-3. [DOI] [PubMed] [Google Scholar]
  • 32.Alberti P, Rossi E, Cornblath DR, et al. Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: Two sides of the same coin. Ann Oncol. 2014;25:257–264. doi: 10.1093/annonc/mdt409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Brundage MD, Pater JL, Zee B. Assessing the reliability of two toxicity scales: Implications for interpreting toxicity data. J Natl Cancer Inst. 1993;85:1138–1148. doi: 10.1093/jnci/85.14.1138. [DOI] [PubMed] [Google Scholar]
  • 34.Koeppen S, Verstappen CC, Körte R, et al. Lack of neuroprotection by an ACTH (4-9) analogue. A randomized trial in patients treated with vincristine for Hodgkin’s or non-Hodgkin’s lymphoma. J Cancer Res Clin Oncol. 2004;130:153–160. doi: 10.1007/s00432-003-0524-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Postma TJ, Heimans JJ, Muller MJ, et al. Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol. 1998;9:739–744. doi: 10.1023/a:1008344507482. [DOI] [PubMed] [Google Scholar]
  • 36.Inoue N, Ishida H, Sano M, et al. Discrepancy between the NCI-CTCAE and DEB-NTC scales in the evaluation of oxaliplatin-related neurotoxicity in patients with metastatic colorectal cancer. Int J Clin Oncol. 2012;17:341–347. doi: 10.1007/s10147-011-0298-z. [DOI] [PubMed] [Google Scholar]
  • 37.Sprowl JA, Ciarimboli G, Lancaster CS, et al. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci USA. 2013;110:11199–11204. doi: 10.1073/pnas.1305321110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Jong NN, Nakanishi T, Liu JJ, et al. Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 2011;338:537–547. doi: 10.1124/jpet.111.181297. [DOI] [PubMed] [Google Scholar]
  • 39.Ip V, Liu JJ, McKeage MJ. Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo. Clin Exp Pharmacol Physiol. 2013;40:371–378. doi: 10.1111/1440-1681.12088. [DOI] [PubMed] [Google Scholar]
  • 40.Liu JJ, Kim Y, Yan F, et al. Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons. Biochem Pharmacol. 2013;85:207–215. doi: 10.1016/j.bcp.2012.10.023. [DOI] [PubMed] [Google Scholar]
  • 41.Ishida S, Lee J, Thiele DJ, et al. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA. 2002;99:14298–14302. doi: 10.1073/pnas.162491399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Safaei R. Role of copper transporters in the uptake and efflux of platinum containing drugs. Cancer Lett. 2006;234:34–39. doi: 10.1016/j.canlet.2005.07.046. [DOI] [PubMed] [Google Scholar]
  • 43.Guminski AD, Balleine RL, Chiew YE, et al. MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma. Gynecol Oncol. 2006;100:239–246. doi: 10.1016/j.ygyno.2005.08.046. [DOI] [PubMed] [Google Scholar]
  • 44.Ip V, Liu JJ, Mercer JF, et al. Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue. Mol Pain. 2010;6:53. doi: 10.1186/1744-8069-6-53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Yamasaki M, Makino T, Masuzawa T, et al. Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma. Br J Cancer. 2011;104:707–713. doi: 10.1038/sj.bjc.6606071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Zhu C, Raber J, Eriksson LA. Hydrolysis process of the second generation platinum-based anticancer drug cis-amminedichlorocyclohexylamineplatinum(II) J Phys Chem B. 2005;109:12195–12205. doi: 10.1021/jp0518916. [DOI] [PubMed] [Google Scholar]
  • 47.Chválová K, Brabec V, Kaspárková J. Mechanism of the formation of DNA-protein cross-links by antitumor cisplatin. Nucleic Acids Res. 2007;35:1812–1821. doi: 10.1093/nar/gkm032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.McDonald ES, Randon KR, Knight A, et al. Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: A potential mechanism for neurotoxicity. Neurobiol Dis. 2005;18:305–313. doi: 10.1016/j.nbd.2004.09.013. [DOI] [PubMed] [Google Scholar]
  • 49.Dzagnidze A, Katsarava Z, Makhalova J, et al. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci. 2007;27:9451–9457. doi: 10.1523/JNEUROSCI.0523-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Ta LE, Espeset L, Podratz J, et al. Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding. Neurotoxicology. 2006;27:992–1002. doi: 10.1016/j.neuro.2006.04.010. [DOI] [PubMed] [Google Scholar]
  • 51.Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: The relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol. 1992;10:795–803. doi: 10.1200/JCO.1992.10.5.795. [DOI] [PubMed] [Google Scholar]
  • 52.McKeage MJ, Hsu T, Screnci D, et al. Nucleolar damage correlates with neurotoxicity induced by different platinum drugs. Br J Cancer. 2001;85:1219–1225. doi: 10.1054/bjoc.2001.2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Namikawa K, Asakura M, Minami T, et al. Toxicity of cisplatin to the central nervous system of male rabbits. Biol Trace Elem Res. 2000;74:223–235. doi: 10.1385/BTER:74:3:223. [DOI] [PubMed] [Google Scholar]
  • 54.Olivi A, Gilbert M, Duncan KL, et al. Direct delivery of platinum-based antineoplastics to the central nervous system: A toxicity and ultrastructural study. Cancer Chemother Pharmacol. 1993;31:449–454. doi: 10.1007/BF00685034. [DOI] [PubMed] [Google Scholar]
  • 55.Adelsberger H, Quasthoff S, Grosskreutz J, et al. The chemotherapeutic oxaliplatin alters voltage-gated Na+ channel kinetics on rat sensory neurons. Eur J Pharmacol. 2000;406:25–32. doi: 10.1016/s0014-2999(00)00667-1. [DOI] [PubMed] [Google Scholar]
  • 56.Grolleau F, Stankiewicz M, Birinyi-Strachan L, et al. Electrophysiological analysis of the neurotoxic action of a funnel-web spider toxin, delta-atracotoxin-HV1a, on insect voltage-gated Na+ channels. J Exp Biol. 2001;204:711–721. doi: 10.1242/jeb.204.4.711. [DOI] [PubMed] [Google Scholar]
  • 57.Sittl R, Lampert A, Huth T, et al. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype NaV1.6-resurgent and persistent current. Proc Natl Acad Sci USA. 2012;109:6704–6709. doi: 10.1073/pnas.1118058109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Dimitrov VG, Arabadzhiev TI, Dimitrova NA, et al. The spectral changes in EMG during a second bout eccentric contraction could be due to adaptation in muscle fibres themselves: A simulation study. Eur J Appl Physiol. 2012;112:1399–1409. doi: 10.1007/s00421-011-2095-9. [DOI] [PubMed] [Google Scholar]
  • 59.Kagiava A, Tsingotjidou A, Emmanouilides C, et al. The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat. Neurotoxicology. 2008;29:1100–1106. doi: 10.1016/j.neuro.2008.09.005. [DOI] [PubMed] [Google Scholar]
  • 60.Mogyoros I, Lin CS, Kuwabara S, et al. Strength-duration properties and their voltage dependence as measures of a threshold conductance at the node of Ranvier of single motor axons. Muscle Nerve. 2000;23:1719–1726. doi: 10.1002/1097-4598(200011)23:11<1719::aid-mus8>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  • 61.Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol. 1998;9:1053–1071. doi: 10.1023/a:1008213732429. [DOI] [PubMed] [Google Scholar]
  • 62.Podratz JL, Knight AM, Ta LE, et al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis. 2011;41:661–668. doi: 10.1016/j.nbd.2010.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Suk R, Gurubhagavatula S, Park S, et al. Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients. Clin Cancer Res. 2005;11:1534–1538. doi: 10.1158/1078-0432.CCR-04-1953. [DOI] [PubMed] [Google Scholar]
  • 64.Argyriou AA, Kyritsis AP, Makatsoris T, et al. Chemotherapy-induced peripheral neuropathy in adults: A comprehensive update of the literature. Cancer Manag Res. 2014;6:135–147. doi: 10.2147/CMAR.S44261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Bergmann TK, Gréen H, Brasch-Andersen C, et al. Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer. Eur J Clin Pharmacol. 2011;67:693–700. doi: 10.1007/s00228-011-1007-6. [DOI] [PubMed] [Google Scholar]
  • 66.Gréen H, Söderkvist P, Rosenberg P, et al. Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol Toxicol. 2009;104:130–137. doi: 10.1111/j.1742-7843.2008.00351.x. [DOI] [PubMed] [Google Scholar]
  • 67.Marsh S, Paul J, King CR, et al. Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: The Scottish Randomised Trial in Ovarian Cancer. J Clin Oncol. 2007;25:4528–4535. doi: 10.1200/JCO.2006.10.4752. [DOI] [PubMed] [Google Scholar]
  • 68.McLeod HL, Sargent DJ, Marsh S, et al. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: Results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol. 2010;28:3227–3233. doi: 10.1200/JCO.2009.21.7943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Cecchin E, D’Andrea M, Lonardi S, et al. A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen. Pharmacogenomics J. 2013;13:403–409. doi: 10.1038/tpj.2012.31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Custodio A, Moreno-Rubio J, Aparicio J, et al. Pharmacogenetic predictors of severe peripheral neuropathy in colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy: A GEMCAD group study. Ann Oncol. 2014;25:398–403. doi: 10.1093/annonc/mdt546. [DOI] [PubMed] [Google Scholar]
  • 71.Won HH, Lee J, Park JO, et al. Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients. Cancer. 2012;118:2828–2836. doi: 10.1002/cncr.26614. [DOI] [PubMed] [Google Scholar]
  • 72.Gamelin L, Capitain O, Morel A, et al. Predictive factors of oxaliplatin neurotoxicity: The involvement of the oxalate outcome pathway. Clin Cancer Res. 2007;13:6359–6368. doi: 10.1158/1078-0432.CCR-07-0660. [DOI] [PubMed] [Google Scholar]
  • 73.Lee KH, Chang HJ, Han SW, et al. Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer. Cancer Chemother Pharmacol. 2013;71:843–851. doi: 10.1007/s00280-013-2075-3. [DOI] [PubMed] [Google Scholar]
  • 74.Inada M, Sato M, Morita S, et al. Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. Int J Clin Pharmacol Ther. 2010;48:729–734. doi: 10.5414/cpp48729. [DOI] [PubMed] [Google Scholar]
  • 75.Kim HS, Kim MK, Chung HH, et al. Genetic polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: A Korean population-based study. Gynecol Oncol. 2009;113:264–269. doi: 10.1016/j.ygyno.2009.01.002. [DOI] [PubMed] [Google Scholar]
  • 76.Fung C, Vaughn DJ, Mitra N, et al. Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF) Front Endocrinol (Lausanne) 2012;3:163. doi: 10.3389/fendo.2012.00163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Hong J, Han SW, Ham HS, et al. Phase II study of biweekly S-1 and oxaliplatin combination chemotherapy in metastatic colorectal cancer and pharmacogenetic analysis. Cancer Chemother Pharmacol. 2011;67:1323–1331. doi: 10.1007/s00280-010-1425-7. [DOI] [PubMed] [Google Scholar]
  • 78.Boige V, Mendiboure J, Pignon JP, et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol. 2010;28:2556–2564. doi: 10.1200/JCO.2009.25.2106. [DOI] [PubMed] [Google Scholar]
  • 79.Caponigro F, Lacombe D, Twelves C, et al. An EORTC phase I study of Bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer. Eur J Cancer. 2009;45:48–55. doi: 10.1016/j.ejca.2008.08.011. [DOI] [PubMed] [Google Scholar]
  • 80.Chen YC, Tzeng CH, Chen PM, et al. Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci. 2010;101:530–535. doi: 10.1111/j.1349-7006.2009.01418.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Goekkurt E, Al-Batran SE, Hartmann JT, et al. Pharmacogenetic analyses of a phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil and leucovorin plus either oxaliplatin or cisplatin: A study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2009;27:2863–2873. doi: 10.1200/JCO.2008.19.1718. [DOI] [PubMed] [Google Scholar]
  • 82.Isla D, Sarries C, Rosell R, et al. Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol. 2004;15:1194–1203. doi: 10.1093/annonc/mdh319. [DOI] [PubMed] [Google Scholar]
  • 83.Keam B, Im SA, Han SW, et al. Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker. BMC Cancer. 2008;8:148. doi: 10.1186/1471-2407-8-148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Khrunin AV, Moisseev A, Gorbunova V, et al. Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. Pharmacogenomics J. 2010;10:54–61. doi: 10.1038/tpj.2009.45. [DOI] [PubMed] [Google Scholar]
  • 85.Ruzzo A, Graziano F, Loupakis F, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 2007;25:1247–1254. doi: 10.1200/JCO.2006.08.1844. [DOI] [PubMed] [Google Scholar]
  • 86.Seo BG, Kwon HC, Oh SY, et al. Comprehensive analysis of excision repair complementation group 1, glutathione S-transferase, thymidylate synthase and uridine diphosphate glucuronosyl transferase 1A1 polymorphisms predictive for treatment outcome in patients with advanced gastric cancer treated with FOLFOX or FOLFIRI. Oncol Rep. 2009;22:127–136. [PubMed] [Google Scholar]
  • 87.Zarate R, Rodríguez J, Bandres E, et al. Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): A dose-finding study and pharmacogenomic analysis. Br J Cancer. 2010;102:987–994. doi: 10.1038/sj.bjc.6605595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Kumamoto K, Ishibashi K, Okada N, et al. Polymorphisms of GSTP1, ERCC2 and TS-3′UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients. Oncol Lett. 2013;6:648–654. doi: 10.3892/ol.2013.1467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Lecomte T, Landi B, Beaune P, et al. Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res. 2006;12:3050–3056. doi: 10.1158/1078-0432.CCR-05-2076. [DOI] [PubMed] [Google Scholar]
  • 90.Oldenburg J, Kraggerud SM, Brydøy M, et al. Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-S-transferase-P1 and -M1, a retrospective cross sectional study. J Transl Med. 2007;5:70. doi: 10.1186/1479-5876-5-70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Stoehlmacher J, Park DJ, Zhang W, et al. Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst. 2002;94:936–942. doi: 10.1093/jnci/94.12.936. [DOI] [PubMed] [Google Scholar]
  • 92.Antonacopoulou AG, Argyriou AA, Scopa CD, et al. Integrin beta-3 L33P: A new insight into the pathogenesis of chronic oxaliplatin-induced peripheral neuropathy? Eur J Neurol. 2010;17:963–968. doi: 10.1111/j.1468-1331.2010.02966.x. [DOI] [PubMed] [Google Scholar]
  • 93.Li QF, Yao RY, Liu KW, et al. Genetic polymorphism of GSTP1: Prediction of clinical outcome to oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. J Korean Med Sci. 2010;25:846–852. doi: 10.3346/jkms.2010.25.6.846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Kanai M, Yoshioka A, Tanaka S, et al. Associations between glutathione S-transferase pi Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy. Cancer Epidemiol. 2010;34:189–193. doi: 10.1016/j.canep.2010.02.008. [DOI] [PubMed] [Google Scholar]
  • 95.Booton R, Ward T, Heighway J, et al. Glutathione-S-transferase P1 isoenzyme polymorphisms, platinum-based chemotherapy, and non-small cell lung cancer. J Thorac Oncol. 2006;1:679–683. [PubMed] [Google Scholar]
  • 96.Kweekel DM, Gelderblom H, Antonini NF, et al. Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients. Eur J Cancer. 2009;45:572–578. doi: 10.1016/j.ejca.2008.10.015. [DOI] [PubMed] [Google Scholar]
  • 97.Paré L, Marcuello E, Altés A, et al. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy. Br J Cancer. 2008;99:1050–1055. doi: 10.1038/sj.bjc.6604671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Argyriou AA, Antonacopoulou AG, Scopa CD, et al. Liability of the voltage-gated sodium channel gene SCN2A R19K polymorphism to oxaliplatin-induced peripheral neuropathy. Oncology. 2009;77:254–256. doi: 10.1159/000236049. [DOI] [PubMed] [Google Scholar]
  • 99.Ashraf T, Kis O, Banerjee N, et al. Drug transporters at brain barriers: Expression and regulation by neurological disorders. Adv Exp Med Biol. 2012;763:20–69. [PubMed] [Google Scholar]
  • 100.Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58. doi: 10.1038/nrc706. [DOI] [PubMed] [Google Scholar]
  • 101.Lolli G, Johnson LN. CAK-cyclin-dependent activating kinase: A key kinase in cell cycle control and a target for drugs? Cell Cycle. 2005;4:572–577. [PubMed] [Google Scholar]
  • 102.Wu G, Cao J, Peng C, et al. Temporal and spatial expression of cyclin H in rat spinal cord injury. Neuromolecular Med. 2011;13:187–196. doi: 10.1007/s12017-011-8150-1. [DOI] [PubMed] [Google Scholar]
  • 103.Weinshilboum RM. Pharmacogenomics: Catechol O-methyltransferase to thiopurine S-methyltransferase. Cell Mol Neurobiol. 2006;26:539–561. doi: 10.1007/s10571-006-9095-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Ross CJ, Katzov-Eckert H, Dubé MP, et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet. 2009;41:1345–1349. doi: 10.1038/ng.478. [DOI] [PubMed] [Google Scholar]
  • 105.Pussegoda K, Ross CJ, Visscher H, et al. Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children. Clin Pharmacol Ther. 2013;94:243–251. doi: 10.1038/clpt.2013.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Peng Z, Wang Q, Gao J, et al. Association between GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy: A systematic review and meta-analysis. Cancer Chemother Pharmacol. 2013;72:305–314. doi: 10.1007/s00280-013-2194-x. [DOI] [PubMed] [Google Scholar]
  • 107.Kweekel DM, Gelderblom H, Guchelaar HJ. Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat Rev. 2005;31:90–105. doi: 10.1016/j.ctrv.2004.12.006. [DOI] [PubMed] [Google Scholar]
  • 108.Zhang X, Jiang LP, Yin Y, et al. XRCC1 and XPD genetic polymorphisms and clinical outcomes of gastric cancer patients treated with oxaliplatin-based chemotherapy: A meta-analysis. Tumour Biol. 2014;35:5637–5645. doi: 10.1007/s13277-014-1746-y. [DOI] [PubMed] [Google Scholar]
  • 109.Ségurel L, Lafosse S, Heyer E, et al. Frequency of the AGT Pro11Leu polymorphism in humans: Does diet matter? Ann Hum Genet. 2010;74:57–64. doi: 10.1111/j.1469-1809.2009.00549.x. [DOI] [PubMed] [Google Scholar]
  • 110.Cavaletti G, Miloso M, Nicolini G, et al. Emerging role of mitogen-activated protein kinases in peripheral neuropathies. J Peripher Nerv Syst. 2007;12:175–194. doi: 10.1111/j.1529-8027.2007.00138.x. [DOI] [PubMed] [Google Scholar]
  • 111.Bianchi R, Gilardini A, Rodriguez-Menendez V, et al. Cisplatin-induced peripheral neuropathy: Neuroprotection by erythropoietin without affecting tumour growth. Eur J Cancer. 2007;43:710–717. doi: 10.1016/j.ejca.2006.09.028. [DOI] [PubMed] [Google Scholar]
  • 112.Cavaletti G, Gilardini A, Canta A, et al. Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat. Exp Neurol. 2007;204:317–325. doi: 10.1016/j.expneurol.2006.11.010. [DOI] [PubMed] [Google Scholar]
  • 113.Meregalli C, Canta A, Carozzi VA, et al. Bortezomib-induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats. Eur J Pain. 2010;14:343–350. doi: 10.1016/j.ejpain.2009.07.001. [DOI] [PubMed] [Google Scholar]
  • 114.Müller LJ, Moorer-van Delft CM, Roubos EW. Snail neurons as a possible model for testing neurotoxic side effects of antitumor agents: Paracrystal formation by Vinca alkaloids. Cancer Res. 1988;48:7184–7188. [PubMed] [Google Scholar]
  • 115.Müller LJ, Moorer-van Delft CM, Roubos EW, et al. Quantitative ultrastructural effects of cisplatin (Platinol), carboplatin (JM8), and iproplatin (JM9) on neurons of freshwater snail Lymnaea stagnalis. Cancer Res. 1992;52:963–973. [PubMed] [Google Scholar]
  • 116.Müller LJ, Moorer-van Delft CM, Zijl R, et al. Use of snail neurons in developing quantitative ultrastructural parameters for neurotoxic side effects of Vinca antitumor agents. Cancer Res. 1990;50:1924–1928. [PubMed] [Google Scholar]
  • 117.DiPaola RS, Schuchter L. Neurologic protection by amifostine. Semin Oncol. 1999;26(suppl 7):82–88. [PubMed] [Google Scholar]
  • 118.Geldof AA. Nerve-growth-factor-dependent neurite outgrowth assay; a research model for chemotherapy-induced neuropathy. J Cancer Res Clin Oncol. 1995;121:657–660. doi: 10.1007/BF01218523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.Geldof AA, Minneboo A, Heimans JJ. Vinca-alkaloid neurotoxicity measured using an in vitro model. J Neurooncol. 1998;37:109–113. doi: 10.1023/a:1005848623771. [DOI] [PubMed] [Google Scholar]
  • 120.Verstappen CC, Geldof AA, Postma TJ, et al. In vitro protection from cisplatin-induced neurotoxicity by amifostine and its metabolite WR1065. J Neurooncol. 1999;44:1–5. doi: 10.1023/a:1006241622639. [DOI] [PubMed] [Google Scholar]
  • 121.Verstappen CC, Postma TJ, Geldof AA, et al. Amifostine protects against chemotherapy-induced neurotoxicity: An in vitro investigation. Anticancer Res. 2004;24:2337–2341. [PubMed] [Google Scholar]
  • 122.Ceresa C, Avan A, Giovannetti E, et al. Characterization of and protection from neurotoxicity induced by oxaliplatin, bortezomib and epothilone-B. Anticancer Res. 2014;34:517–523. [PubMed] [Google Scholar]
  • 123.Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:1941–1967. doi: 10.1200/JCO.2013.54.0914. [DOI] [PubMed] [Google Scholar]
  • 124.Lin CH, Kuo SC, Huang LJ, et al. Neuroprotective effect of N-acetylcysteine on neuronal apoptosis induced by a synthetic gingerdione compound: Involvement of ERK and p38 phosphorylation. J Neurosci Res. 2006;84:1485–1494. doi: 10.1002/jnr.21047. [DOI] [PubMed] [Google Scholar]
  • 125.Guo Y, Jones D, Palmer JL, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2014;22:1223–1231. doi: 10.1007/s00520-013-2075-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Lu P, Fan QX, Wang LX, et al. [Prophylactic effect of amifostine on oxaliplatin-related neurotoxicity in patients with digestive tract tumors] Ai Zheng. 2008;27:1117–1120. [PubMed] [Google Scholar]
  • 127.De Vos FY, Bos AM, Schaapveld M, et al. A randomized phase II study of paclitaxel with carboplatin +/− amifostine as first line treatment in advanced ovarian carcinoma. Gynecol Oncol. 2005;97:60–67. doi: 10.1016/j.ygyno.2004.11.052. [DOI] [PubMed] [Google Scholar]
  • 128.Hilpert F, Stähle A, Tomé O, et al. Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer with carboplatin/paclitaxel-based chemotherapy: A double-blind, placebo-controlled, randomized phase II study from the Arbeitsgemeinschaft Gynäkologische Onkologoie (AGO) Ovarian Cancer Study Group. Support Care Cancer. 2005;13:797–805. doi: 10.1007/s00520-005-0782-y. [DOI] [PubMed] [Google Scholar]
  • 129.Kanat O, Evrensel T, Baran I, et al. Protective effect of amifostine against toxicity of paclitaxel and carboplatin in non-small cell lung cancer: A single center randomized study. Med Oncol. 2003;20:237–245. doi: 10.1385/MO:20:3:237. [DOI] [PubMed] [Google Scholar]
  • 130.Leong SS, Tan EH, Fong KW, et al. Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 2003;21:1767–1774. doi: 10.1200/JCO.2003.11.005. [DOI] [PubMed] [Google Scholar]
  • 131.Lorusso D, Ferrandina G, Greggi S, et al. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients. Ann Oncol. 2003;14:1086–1093. doi: 10.1093/annonc/mdg301. [DOI] [PubMed] [Google Scholar]
  • 132.Gallardo D, Mohar A, Calderillo G, et al. Cisplatin, radiation, and amifostine in carcinoma of the uterine cervix. Int J Gynecol Cancer. 1999;9:225–230. doi: 10.1046/j.1525-1438.1999.99029.x. [DOI] [PubMed] [Google Scholar]
  • 133.Planting AS, Catimel G, de Mulder PH, et al. Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer. Ann Oncol. 1999;10:693–700. doi: 10.1023/a:1008353505916. [DOI] [PubMed] [Google Scholar]
  • 134.Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: Results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol. 1996;14:2101–2112. doi: 10.1200/JCO.1996.14.7.2101. [DOI] [PubMed] [Google Scholar]
  • 135.Miller AA, Wang XF, Gu L, et al. Phase II randomized study of dose-dense docetaxel and cisplatin every 2 weeks with pegfilgrastim and darbepoetin alfa with and without the chemoprotector BNP7787 in patients with advanced non-small cell lung cancer (CALGB 30303) J Thorac Oncol. 2008;3:1159–1165. doi: 10.1097/JTO.0b013e318186fb0d. [DOI] [PubMed] [Google Scholar]
  • 136.Han CH, Khwaounjoo P, Kilfoyle DH, et al. Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients. BMC Cancer. 2013;13:495. doi: 10.1186/1471-2407-13-495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137.Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance) J Clin Oncol. 2014;32:997–1005. doi: 10.1200/JCO.2013.52.0536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138.Grothey A, Nikcevich DA, Sloan JA, et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011;29:421–427. doi: 10.1200/JCO.2010.31.5911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139.Knijn N, Tol J, Koopman M, et al. The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatin-based systemic treatment in advanced colorectal cancer patients. Eur J Cancer. 2011;47:369–374. doi: 10.1016/j.ejca.2010.10.006. [DOI] [PubMed] [Google Scholar]
  • 140.Ishibashi K, Okada N, Miyazaki T, et al. Effect of calcium and magnesium on neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6 therapy: A prospective randomized study. Int J Clin Oncol. 2010;15:82–87. doi: 10.1007/s10147-009-0015-3. [DOI] [PubMed] [Google Scholar]
  • 141.Chay WY, Tan SH, Lo YL, et al. Use of calcium and magnesium infusions in prevention of oxaliplatin induced sensory neuropathy. Asia Pac J Clin Oncol. 2010;6:270–277. doi: 10.1111/j.1743-7563.2010.01344.x. [DOI] [PubMed] [Google Scholar]
  • 142.von Delius S, Eckel F, Wagenpfeil S, et al. Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: Final results of a randomised, controlled, multicenter phase II study. Invest New Drugs. 2007;25:173–180. doi: 10.1007/s10637-006-9010-y. [DOI] [PubMed] [Google Scholar]
  • 143.Gandara DR, Nahhas WA, Adelson MD, et al. Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. J Clin Oncol. 1995;13:490–496. doi: 10.1200/JCO.1995.13.2.490. [DOI] [PubMed] [Google Scholar]
  • 144.Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. The Oncologist. 2007;12:312–319. doi: 10.1634/theoncologist.12-3-312. [DOI] [PubMed] [Google Scholar]
  • 145.Leal AD, Qin R, Atherton PJ, et al. North Central Cancer Treatment Group/Alliance trial N08CA: The use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled study. Cancer. 2014;120:1890–1897. doi: 10.1002/cncr.28654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 146.Milla P, Airoldi M, Weber G, et al. Administration of reduced glutathione in FOLFOX4 adjuvant treatment for colorectal cancer: Effect on oxaliplatin pharmacokinetics, Pt-DNA adduct formation, and neurotoxicity. Anticancer Drugs. 2009;20:396–402. doi: 10.1097/CAD.0b013e32832a2dc1. [DOI] [PubMed] [Google Scholar]
  • 147.Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20:3478–3483. doi: 10.1200/JCO.2002.07.061. [DOI] [PubMed] [Google Scholar]
  • 148.Schmidinger M, Budinsky AC, Wenzel C, et al. Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer. Wien Klin Wochenschr. 2000;112:617–623. [PubMed] [Google Scholar]
  • 149.Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomised trial. Ann Oncol. 1997;8:569–573. doi: 10.1023/a:1008211226339. [DOI] [PubMed] [Google Scholar]
  • 150.Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. J Clin Oncol. 1995;13:26–32. doi: 10.1200/JCO.1995.13.1.26. [DOI] [PubMed] [Google Scholar]
  • 151.Colombo N, Bini S, Miceli D, et al. Weekly cisplatin +/− glutathione in relapsed ovarian carcinoma. Int J Gynecol Cancer. 1995;5:81–86. doi: 10.1046/j.1525-1438.1995.05020081.x. [DOI] [PubMed] [Google Scholar]
  • 152.Bogliun G, Marzorati L, Cavaletti G, et al. Evaluation by somatosensory evoked potentials of the neurotoxicity of cisplatin alone or in combination with glutathione. Ital J Neurol Sci. 1992;13:643–647. doi: 10.1007/BF02334967. [DOI] [PubMed] [Google Scholar]
  • 153.Kono T, Hata T, Morita S, et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): A phase 2, multicenter, randomized, double‑blind, placebo‑controlled trial of goshajinkigan to prevent oxaliplatin‑induced neuropathy. Cancer Chemother Pharmacol. 2013;72:1283–1290. doi: 10.1007/s00280-013-2306-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Nishioka M, Shimada M, Kurita N, et al. The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. Int J Clin Oncol. 2011;16:322–327. doi: 10.1007/s10147-010-0183-1. [DOI] [PubMed] [Google Scholar]
  • 155.Cassidy J, Paul J, Soukop M, et al. Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin. Cancer Chemother Pharmacol. 1998;41:161–166. doi: 10.1007/s002800050723. [DOI] [PubMed] [Google Scholar]
  • 156.Roberts JA, Jenison EL, Kim K, et al. A randomized, multicenter, double-blind, placebo-controlled, dose-finding study of ORG 2766 in the prevention or delay of cisplatin-induced neuropathies in women with ovarian cancer. Gynecol Oncol. 1997;67:172–177. doi: 10.1006/gyno.1997.4832. [DOI] [PubMed] [Google Scholar]
  • 157.van Gerven JM, Hovestadt A, Moll JW, et al. The effects of an ACTH (4-9) analogue on development of cisplatin neuropathy in testicular cancer: A randomized trial. J Neurol. 1994;241:432–435. doi: 10.1007/BF00900961. [DOI] [PubMed] [Google Scholar]
  • 158.Hovestadt A, van der Burg ME, Verbiest HB, et al. The course of neuropathy after cessation of cisplatin treatment, combined with Org 2766 or placebo. J Neurol. 1992;239:143–146. doi: 10.1007/BF00833914. [DOI] [PubMed] [Google Scholar]
  • 159.van der Hoop RG, Vecht CJ, van der Burg ME, et al. Prevention of cisplatin neurotoxicity with an ACTH(4-9) analogue in patients with ovarian cancer. N Engl J Med. 1990;322:89–94. doi: 10.1056/NEJM199001113220204. [DOI] [PubMed] [Google Scholar]
  • 160.Argyriou AA, Chroni E, Polychronopoulos P, et al. Efficacy of oxcarbazepine for prophylaxis against cumulative oxaliplatin-induced neuropathy. Neurology. 2006;67:2253–2255. doi: 10.1212/01.wnl.0000249344.99671.d4. [DOI] [PubMed] [Google Scholar]
  • 161.Arrieta O, García-Navarrete R, Zúñiga S, et al. Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice. Eur J Clin Invest. 2005;35:201–207. doi: 10.1111/j.1365-2362.2005.01467.x. [DOI] [PubMed] [Google Scholar]
  • 162.Davis ID, Kiers L, MacGregor L, et al. A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy. Clin Cancer Res. 2005;11:1890–1898. doi: 10.1158/1078-0432.CCR-04-1655. [DOI] [PubMed] [Google Scholar]
  • 163.Durand JP, Deplanque G, Montheil V, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: Results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2012;23:200–205. doi: 10.1093/annonc/mdr045. [DOI] [PubMed] [Google Scholar]
  • 164.Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: Results of a randomized phase III clinical trial. Support Care Cancer. 2011;19:1769–1777. doi: 10.1007/s00520-010-1018-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 165.Pace A, Giannarelli D, Galiè E, et al. Vitamin E neuroprotection for cisplatin neuropathy: A randomized, placebo-controlled trial. Neurology. 2010;74:762–766. doi: 10.1212/WNL.0b013e3181d5279e. [DOI] [PubMed] [Google Scholar]
  • 166.Argyriou AA, Chroni E, Koutras A, et al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: Final results. Support Care Cancer. 2006;14:1134–1140. doi: 10.1007/s00520-006-0072-3. [DOI] [PubMed] [Google Scholar]
  • 167.Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 2003;21:927–931. doi: 10.1200/JCO.2003.05.139. [DOI] [PubMed] [Google Scholar]
  • 168.Cassidy J, Bjarnason GA, Hickish T, et al. Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC) J Clin Oncol. 2006;24(suppl 18):3507a. [Google Scholar]
  • 169.Harned TM, Kalous O, Neuwelt A, et al. Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity. Clin Cancer Res. 2008;14:533–540. doi: 10.1158/1078-0432.CCR-06-2289. [DOI] [PubMed] [Google Scholar]
  • 170.Muldoon LL, Pagel MA, Kroll RA, et al. Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res. 2000;6:309–315. [PubMed] [Google Scholar]
  • 171.Dickey DT, Wu YJ, Muldoon LL, et al. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol Exp Ther. 2005;314:1052–1058. doi: 10.1124/jpet.105.087601. [DOI] [PubMed] [Google Scholar]
  • 172.Maibach R, Childs M, Rajput K, et al. SIOPEL 6: A multicenter open-label randomized phase III trial of the efficacy of sodium thiosulphate (STS) in reducing ototoxicity in patients receiving cisplatin (Cis) monotherapy for standard-risk hepatoblastoma (SR-HB) J Clin Oncol. 2014;32(suppl 5):TPS10094a. [Google Scholar]
  • 173.Freyer DR. The effects of sodium thiosulfate (STS) on cisplatin-induced hearing loss: A report from the Children’s Oncology Group. J Clin Oncol. 2014;32(suppl 5):10017a. [Google Scholar]
  • 174.Parker AR, Petluru PN, Wu M, et al. BNP7787-mediated modulation of paclitaxel- and cisplatin-induced aberrant microtubule protein polymerization in vitro. Mol Cancer Ther. 2010;9:2558–2567. doi: 10.1158/1535-7163.MCT-10-0300. [DOI] [PubMed] [Google Scholar]
  • 175.De Santis S, Pace A, Bove L, et al. Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor. Clin Cancer Res. 2000;6:90–95. [PubMed] [Google Scholar]
  • 176.Schmidt Y, Unger JW, Bartke I, et al. Effect of nerve growth factor on peptide neurons in dorsal root ganglia after taxol or cisplatin treatment and in diabetic (db/db) mice. Exp Neurol. 1995;132:16–23. doi: 10.1016/0014-4886(95)90054-3. [DOI] [PubMed] [Google Scholar]
  • 177.Scuteri A, Galimberti A, Ravasi M, et al. NGF protects dorsal root ganglion neurons from oxaliplatin by modulating JNK/Sapk and ERK1/2. Neurosci Lett. 2010;486:141–145. doi: 10.1016/j.neulet.2010.09.028. [DOI] [PubMed] [Google Scholar]
  • 178.Corcoran J, Maden M. Nerve growth factor acts via retinoic acid synthesis to stimulate neurite outgrowth. Nat Neurosci. 1999;2:307–308. doi: 10.1038/7214. [DOI] [PubMed] [Google Scholar]
  • 179.Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer. 2005;41:1746–1750. doi: 10.1016/j.ejca.2005.04.028. [DOI] [PubMed] [Google Scholar]
  • 180.De Grandis D. Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: A short review. CNS Drugs. 2007;21(suppl 1):39–46. doi: 10.2165/00023210-200721001-00006. [DOI] [PubMed] [Google Scholar]
  • 181.Ghirardi O, Lo Giudice P, Pisano C, et al. Acetyl-L-carnitine prevents and reverts experimental chronic neurotoxicity induced by oxaliplatin, without altering its antitumor properties. Anticancer Res. 2005;25:2681–2687. [PubMed] [Google Scholar]
  • 182.Gwag BJ, Sessler FM, Robine V, et al. Endogenous glutamate levels regulate nerve growth factor mRNA expression in the rat dentate gyrus. Mol Cells. 1997;7:425–430. [PubMed] [Google Scholar]
  • 183.Taglialatela G, Navarra D, Cruciani R, et al. Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats. Exp Gerontol. 1994;29:55–66. doi: 10.1016/0531-5565(94)90062-0. [DOI] [PubMed] [Google Scholar]
  • 184.Bianchi R, Brines M, Lauria G, et al. Protective effect of erythropoietin and its carbamylated derivative in experimental cisplatin peripheral neurotoxicity. Clin Cancer Res. 2006;12:2607–2612. doi: 10.1158/1078-0432.CCR-05-2177. [DOI] [PubMed] [Google Scholar]
  • 185.Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305:239–242. doi: 10.1126/science.1098313. [DOI] [PubMed] [Google Scholar]
  • 186.Arrieta Ó, Hernández-Pedro N, Fernández-González-Aragón MC, et al. Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer. Neurology. 2011;77:987–995. doi: 10.1212/WNL.0b013e31822e045c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 187.Ibrahimpasic K. Alpha lipoic acid and glycaemic control in diabetic neuropathies at type 2 diabetes treatment. Med Arh. 2013;67:7–9. doi: 10.5455/medarh.2013.67.7-9. [DOI] [PubMed] [Google Scholar]
  • 188.Barhwal K, Hota SK, Prasad D, et al. Hypoxia-induced deactivation of NGF-mediated ERK1/2 signaling in hippocampal cells: Neuroprotection by acetyl-L-carnitine. J Neurosci Res. 2008;86:2705–2721. doi: 10.1002/jnr.21722. [DOI] [PubMed] [Google Scholar]
  • 189.Gopal KV, Wu C, Shrestha B, et al. d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks. Neurotoxicol Teratol. 2012;34:495–504. doi: 10.1016/j.ntt.2012.06.002. [DOI] [PubMed] [Google Scholar]
  • 190.Schmutz M, Brugger F, Gentsch C, et al. Oxcarbazepine: Preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia. 1994;35(suppl 5):S47–S50. doi: 10.1111/j.1528-1157.1994.tb05967.x. [DOI] [PubMed] [Google Scholar]
  • 191.Barhwal K, Hota SK, Jain V, et al. Acetyl-l-carnitine (ALCAR) prevents hypobaric hypoxia-induced spatial memory impairment through extracellular related kinase-mediated nuclear factor erythroid 2-related factor 2 phosphorylation. Neuroscience. 2009;161:501–514. doi: 10.1016/j.neuroscience.2009.02.086. [DOI] [PubMed] [Google Scholar]
  • 192.Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-l-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol. 2013;31:2627–2633. doi: 10.1200/JCO.2012.44.8738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 193.Susman E. Xaliproden lessens oxaliplatin-mediated neuropathy. Lancet Oncol. 2006;7:288. doi: 10.1016/s1470-2045(06)70639-8. [DOI] [PubMed] [Google Scholar]
  • 194.Nagaki Y, Hayasaka S, Hayasaka Y, et al. Effects of goshajinkigan on corneal sensitivity, superficial punctate keratopathy and tear secretion in patients with insulin-dependent diabetes mellitus. Am J Chin Med. 2003;31:103–109. doi: 10.1142/S0192415X03000771. [DOI] [PubMed] [Google Scholar]
  • 195.Kono T, Mishima H, Shimada M, et al. Preventive effect of goshajinkigan on peripheral neurotoxicity of FOLFOX therapy: A placebo-controlled double-blind randomized phase II study (the GONE Study) Jpn J Clin Oncol. 2009;39:847–849. doi: 10.1093/jjco/hyp100. [DOI] [PubMed] [Google Scholar]
  • 196.Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: Diagnosis, treatment, and prevention. Neuro-oncol. 2012;14(suppl 4):iv45–iv54. doi: 10.1093/neuonc/nos203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 197.Kaur G, Phillips C, Wong K, et al. Timing is important in medication administration: A timely review of chronotherapy research. Int J Clin Pharmacol. 2013;35:344–358. doi: 10.1007/s11096-013-9749-0. [DOI] [PubMed] [Google Scholar]
  • 198.Mormont MC, Lévi F. Circadian-system alterations during cancer processes: A review. Int J Cancer. 1997;70:241–247. doi: 10.1002/(sici)1097-0215(19970117)70:2<241::aid-ijc16>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  • 199.Liao C, Li J, Bin Q, et al. Chronomodulated chemotherapy versus conventional chemotherapy for advanced colorectal cancer: A meta-analysis of five randomized controlled trials. Int J Colorectal Dis. 2010;25:343–350. doi: 10.1007/s00384-009-0838-4. [DOI] [PubMed] [Google Scholar]
  • 200.Cavaletti G. Calcium and magnesium prophylaxis for oxaliplatin-related neurotoxicity: Is it a trade-off between drug efficacy and toxicity? The Oncologist. 2011;16:1667–1668. doi: 10.1634/theoncologist.2011-0343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 201.Khattak MA. Calcium and magnesium prophylaxis for oxaliplatin-related neurotoxicity: Is it a trade-off between drug efficacy and toxicity? The Oncologist. 2011;16:1780–1783. doi: 10.1634/theoncologist.2011-0157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 202.Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA. 2013;309:1359–1367. doi: 10.1001/jama.2013.2813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 203.Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain. 2002;98:195–203. doi: 10.1016/s0304-3959(02)00047-7. [DOI] [PubMed] [Google Scholar]
  • 204.Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3) Cancer. 2007;110:2110–2118. doi: 10.1002/cncr.23008. [DOI] [PubMed] [Google Scholar]
  • 205.Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer. 2008;112:2802–2808. doi: 10.1002/cncr.23482. [DOI] [PubMed] [Google Scholar]
  • 206.Barton DL, Wos EJ, Qin R, et al. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer. 2011;19:833–841. doi: 10.1007/s00520-010-0911-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

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