Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.

Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir.

Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m² oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m² oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m² oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders.

Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients.

Trial registration. Clinicaltrials.gov NCT00727922.

Funding. Université Paris Descartes, Ministère de la Recherche et de l’Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.

The activity of platinum drugs is attributed to the formation of adducts with DNA that lead to cell death and intracellular generation of ROS following DNA and mitochondrial lesions (1). Oxaliplatin, a third-generation organoplatinum, also interacts with reduced glutathione (GSH), and the depletion of GSH is one of the pathways through which platinum-based cytotoxic drugs generate ROS in malignant cells (2).

Peripheral neuropathy occurs in 85%–95% of all patients exposed to oxaliplatin (3). This side effect may limit the dosage and/or duration of administration of the drug (4). The onset of acute neuropathy immediately follows administration of the drug, with paresthesias and possibly muscle cramps in the hands or feet generally reversible within hours or days. Electrophysiological studies have shown the hyperexcitability of peripheral nerves (5). The chronic form is characterized by the persistence of symptoms and distal sensory axonal degeneration, with myelin loss involving large fibers in the absence of a motor component (6). The occurrence of paresthesias and dysesthesias immediately after drug administration suggests a direct effect on the nerves. Several clinical and electrophysiological features of the acute form are similar to those of neuromyotonia, which is characterized by the impairment of cellular voltage-gated K⁺ channels (5). Although most ex vivo and in vivo investigations have confirmed an oxaliplatin-induced “channelopathy,” there is no evidence yet that a dysfunction of voltage-gated channels is the specific causal factor of the neuropathy. The acute effects of oxaliplatin can also be caused by the chelation of calcium by oxalate released from oxaliplatin and its effects on neural membranes and synapses (7). Chronic neuropathy results from the accumulation of platinum in dorsal root ganglion cells (8), and the repeated oxidative stress can be an important pathogenetic mechanism (9). Neither calcium or magnesium infusions, nor neuromodulatory agents have proved sufficiently effective to become routine treatments of acute or chronic neuropathy (10, 11). An alternative therapeutic approach is to target an upstream phenomenon, that is, the generation of oxidative stress by oxaliplatin. Indeed, in 1990, Mollman et al. observed that cisplatin-induced neuropathy is clinically indistinguishable from the neuropathy observed in patients with vitamin E deficiency (12). Since vitamin E is an antioxidant that maintains lipid-rich neural membranes, a molecule able to detoxify the ROS generated by oxaliplatin could prevent the drug’s neurotoxicity (13). A clinical trial conducted by Cascinu et al. showed limited efficacy of GSH infusions in oxaliplatin-treated patients (14). However, the efficacy was probably limited by the inability of GSH to cross cell membranes. This led us to try another molecule, mangafodipir.

Mangafodipir is a chelate of manganese and of the ligand fodipir, a vitamin B6 derivative. Vitamin B6 is known for its ability to maintain normal neurological functions and for its neuroprotective activity (15). In addition, given that mangafodipir is endowed with SOD-, catalase-, and glutathione reductase–like (GR-like) properties, it can target multiple steps of the ROS cascade by detoxifying superoxide anions and hydrogen peroxide and by restoring GSH (16, 17). Moreover, this molecule is known to cross the cell membrane, and we have already shown its ability to improve the therapeutic index of oxaliplatin (18).

We first designed a mouse model of oxaliplatin-induced neuropathy and tested the preventive and curative effects of mangafodipir on the clinical and electrophysiological signs and oxidative stress. Given the positive results obtained in the animal model, a phase II clinical trial was designed to include patients with cancer and oxaliplatin-induced neuropathy.

Mangafodipir prevented oxaliplatin-induced locomotor disturbances in mice with oxaliplatin-induced neuropathy. We studied locomotor dysfunction in mice using the rotarod test. After 8 weeks, mice injected weekly with oxaliplatin (10 mg/kg; n = 8) displayed a decreased latency to fall (514 ± 120 seconds) versus mice receiving vehicle alone (n = 8, 1,073 ± 106 seconds; P = 0.006). In contrast, injections of oxaliplatin plus mangafodipir had no effect on the latency to fall (at 8 weeks: 961 ± 137 seconds with oxaliplatin plus mangafodipir versus 1,073 ± 106 seconds with vehicle; P = 0.505 and 1,217 ± 201 seconds with mangafodipir alone; P = 0.598) (Figure 1A).

Figure 1

In vivo study of oxaliplatin-induced neurotoxicity. Experimental mice received oxaliplatin (10 mg/kg) weekly and mangafodipir (10 mg/kg) 3 times a week for 8 weeks. Evaluation of hyperalgesia required two 5-day cycles of daily oxaliplatin (3 mg/kg). Control mice received either oxaliplatin or vehicle alone. Locomotor disturbances, cold hypoesthesia, nociception, or cold hyperalgesia were evaluated using rotarod testing, cold plate testing at +4°C, von Frey tests, or cold plate testing at –4°C, respectively (A–D). MnTBAP (10 mg/kg) or vitamin B6 (10 mg/kg), two components of mangafodipir, were substituted for mangafodipir, and mice were tested under the same experimental conditions (E–H). Data are presented as the means ± SEM of 8 different mice under each condition. *P < 0.05 and **P < 0.01 versus vehicle.

Mangafodipir prevented oxaliplatin-induced cold hypoesthesia. We studied cold hypoesthesia in mice injected weekly with 10 mg/kg of oxaliplatin on a cold plate set at +4°C ± 0.2°C. By 8 weeks, oxaliplatin increased the latency to escape evaluated on a cold plate (n = 8, 108 ± 11 seconds) versus vehicle alone (16 ± 3 seconds; P = 0.002) or mangafodipir alone (21 ± 3 seconds, P = 0.006). We found that mangafodipir abrogated the alterations induced by oxaliplatin (43 ± 5 seconds with oxaliplatin plus mangafodipir versus 108 ± 11 seconds with oxaliplatin alone, P = 0.005) (Figure 1B).

Mangafodipir prevented oxaliplatin-induced nociception. A von Frey test at 8 weeks showed that the threshold of withdrawal of the touched paw was higher in mice treated with oxaliplatin (n = 8, 8.2 ± 0.5 g) than in mice treated with vehicle alone (1.1 ± 0.2 g; P = 0.002) (Figure 1C). Mangafodipir corrected the hypoesthesia observed in the von Frey test (1.36 ± 0.25 g with oxaliplatin plus mangafodipir versus 8.2 ± 0.5 g with oxaliplatin alone, P = 0.002) (Figure 1C).

Mangafodipir prevented oxaliplatin-induced cold hyperalgesia. Cold hyperalgesia was studied on a cold plate set at –4°C ± 0.2°C in mice treated daily with 3 mg/kg of oxaliplatin. After 5 days of treatment (oxaliplatin cycle 1), the mean number of brisk lifts of either hind paw was higher in mice that were injected daily with oxaliplatin (n = 10, 20 ± 1.4 paw lifts) than in mice injected with vehicle alone (n = 10, 11 ± 1.1 paw lifts; P = 0.0003). We observed the same changes after the second cycle of treatment. The association of mangafodipir with oxaliplatin prevented an increase in the number of paw lifts (n = 10, 12 ± 1.0 after the first cycle and 13 ± 1.2 after the second cycle; P = 0.90 and P = 0.97 versus vehicle) (Figure 1D).

The preventive effects of mangafodipir on oxaliplatin-induced neuropathy are mediated by its antioxidant properties. We explored separately the activities of the two components of mangafodipir using MnTBAP, a chelate of manganese with superoxide dismutase and catalase activities, and vitamin B6 (Figure 1, E–H). As we had already observed, after 8 weeks, oxaliplatin (10 mg/kg, once a week) induced locomotor disturbances (latency to fall: 514 ± 120 seconds), cold hypoesthesia (latency to escape: 108 ± 11 seconds), and increased the threshold of paw withdrawal (8.20 ± 0.5 g). After 8 weeks, we observed that the antioxidant MnTBAP (10 mg/kg, 3 times per week) in addition to oxaliplatin prevented locomotor disturbances (latency to fall: 961 ± 137 seconds; P = 0.032 versus oxaliplatin alone), cold hypoesthesia (latency to escape: 43 ± 5 seconds; P = 0.00058 versus oxaliplatin alone), and an increase in the paw withdrawal threshold (1.36 ± 0.5 g; P < 0.0001 versus oxaliplatin alone). We found that vitamin B6 had no effect on the neuropathy.

Mangafodipir prevented oxaliplatin-induced neuromuscular hyperexcitability in mice. We studied the multimodal excitability of the neuromuscular system to characterize the effects of oxaliplatin and mangafodipir. We performed excitability tests (stimulus-response, strength-duration, and current-threshold relationships, as well as the threshold electrotonus and recovery cycle) on the compound muscle action potential (CMAP) recorded in the plantar muscles of mice injected with vehicle, oxaliplatin, mangafodipir, or oxaliplatin plus mangafodipir for 2 and 4 weeks (Table 1 and Supplemental Figure 1; supplemental material available online with this article; doi: 10.1172/JCI68730DS1). Off-line treatment of CMAP recordings from mice injected over a 2-week period with either oxaliplatin or mangafodipir, or oxaliplatin plus mangafodipir revealed no markedly abnormal excitability waveform features compared with those of vehicle-injected mice. We confirmed this finding by analyzing the data gained from the five excitability tests (Table 1).

Table 1

Excitability parameters derived from plantar muscle recordings of mice injected for 15 and 30 days (means ± SEM, n = 8 mice in each group) with vehicle, oxaliplatin, mangafodipir, or mangafodipir plus oxaliplatin

In contrast, the recordings made after 4 weeks of oxaliplatin injections showed alterations in neuromuscular excitability and lower body weight compared with the vehicle-injected animals. These alterations consisted of (a) a reduction in the resting slope (Table 1 and Supplemental Figure 1A), suggesting that fewer ion channels were open at the resting membrane potential; (b) an increase in threshold changes in response to both depolarizing and hyperpolarizing currents (Table 1 and Supplemental Figure 1C), likely caused by a reduced potassium conductance; and (c) greater superexcitability and lower subexcitability (Table 1 and Supplemental Figure 1D), indicative of potassium channel dysfunction. Consistent with membrane hyperexcitability, we did not detect these modifications by 4 weeks in the recordings from mice injected with oxaliplatin plus mangafodipir or with mangafodipir alone.

Morphological characterization of mangafodipir effects on oxaliplatin-induced neuropathy in mice. We examined the myelinated axons of sciatic nerves using confocal laser scanning microscopy for optical sectioning followed by 3D reconstruction of myelinated nerve fibers (Figure 2A). The mean values of the three parameters obtained from mice injected for 8 weeks with oxaliplatin revealed a marked decrease in the internodal diameter (P = 0.010), which may reflect a preferential loss of large myelinated nerve fibers. The absence of nodal length modification (P = 0.597) we observed suggests either a preferential loss of large myelinated nerve fibers or an alteration in myelin sheet layers surrounding the axons (Table 2 and Figure 2B). The tendency of nodal length to increase compared with that seen in vehicle-injected animals (P = 0.097, Table 2) is a consequence of membrane hyperexcitability. We did not detect any of these modifications in mice injected for 8 weeks with oxaliplatin plus mangafodipir or with mangafodipir alone.

Figure 2

Morphological characterization of single myelinated nerve fibers isolated from the sciatic nerves of mice injected with vehicle, oxaliplatin, oxaliplatin plus mangafodipir (Ox + M), or mangafodipir (M) for 44 days. (A) Typical confocal microscopic images under each condition of single nerve fibers acquired by transmitted light (left panels) and of 3D reconstructions by projections of a series of optical sections from single nerve fibers stained with FM1-43 (right panels). The circles indicate the nodes of Ranvier examined. Original magnification, ×3,500. (B) Schematic representation of a single myelinated axon showing the measured morphological parameters: internodal diameter (Di), nodal diameter (Dn), and nodal length (Ln).

Table 2

Mean values of morphological parameters ± SEM of 88 to 107 nerve fibers from 8 different mice under each condition

Effect of mangafodipir on oxidative stress in mice treated with oxaliplatin. We determined the advanced oxidized protein products (AOPPs) every 2 weeks in the serum of control and experimental mice. Serum levels remained unchanged in control mice injected with vehicle or mangafodipir (Supplemental Figure 2). In mice injected with oxaliplatin, AOPP levels (μM chloramine T equivalents) increased from week 4 onward (by week 6: 1.83 ± 0.16 μM versus 1.04 ± 0.15 μM in control mice; P = 0.005). We found that the association of mangafodipir with oxaliplatin reduced serum AOPPs (by week 6: 1.50 ± 0.15 μM versus 1.83 ± 0.16 μM in oxaliplatin-treated mice; P = 0.05).

Effect of mangafodipir in patients with oxaliplatin-induced neuropathy: clinical trial. The phase II clinical trial, which included 23 patients, started in June 2008 and concluded in April 2011. Table 3 details the patients’ baseline characteristics. The oxaliplatin-related neuropathic effects were evaluated in terms of sensitivity to cold objects, discomfort when swallowing cold liquids, throat discomfort, and muscle cramps. The CONSORT flow diagram of patients for whom the treatment was stopped for grade >2 sensory neurotoxicity is shown in Figure 3. The primary endpoint was reached in 77% of patients (17 of 22 patients treated) whose neuropathy improved or stabilized after 4 cycles of mangafodipir and chemotherapy. Mangafodipir reduced the incidence of grade ≥2 neuropathy in 7 of the 22 patients treated (32%) despite the continuation of oxaliplatin for 8 cycles. While at the time of inclusion in the study all patients had grade ≥2 neuropathy, 6 of the 7 patients treated with oxaliplatin and mangafodipir for 8 cycles had grade 0 to 1 neuropathy (Figure 4A). Neuropathy worsened in 6 nonresponder patients, 3 before the fourth cycle and 3 at a later point. Nine patients were excluded because of disease progression that precluded the continuation of oxaliplatin.

Figure 3

CONSORT statement flow diagram of patients included in the study. n, number of patients.

Figure 4

Sensory neurotoxicity improves with cumulative oxaliplatin plus mangafodipir treatment. (A) Biological changes in the sera of patients treated with oxaliplatin plus mangafodipir. Plasma manganese changes (B). Oxidative stress markers prior to chemotherapy for serum levels of AOPPs (C), plasma SOD activity (D), GR (E), and thiols (F).

Table 3

Baseline characteristics of cancer patients treated with mangafodipir and oxaliplatin-based chemotherapy

We observed no significant alterations in hematological or biochemical parameters following the introduction of mangafodipir, except for a significant increase in neutrophil cell counts (P = 0.010), a decrease in hemoglobin levels (P < 0.001), and an increase in alkaline phosphatase levels (P < 0.001) (Table 4). Plasma concentrations of manganese remained steady (Figure 4B). In the absence of worsening of neuropathy, oxaliplatin treatment was continued, allowing a median additional progression-free survival of 2.75 months (Figure 5A). Overall survival of patients receiving mangafodipir plus oxaliplatin-based chemotherapy was 33.2 months (Figure 5B).

Figure 5

Survival rates of patients treated with oxaliplatin plus mangafodipir. Progression-free survival (A) and overall survival (B). Cumulative doses of oxaliplatin administered to patients in each group (C).

Table 4

Biological changes in sera of patients treated with oxaliplatin plus mangafodipir

Effect of mangafodipir on the cumulative dose of oxaliplatin in patients with neuropathy. The patients enrolled in the study received a mean dose of 880 ± 239 mg/m² of oxaliplatin prior to inclusion. During the trial, the dosage of oxaliplatin was maintained at 85 mg/m². Thus, the patients treated with mangafodipir were exposed to a mean additional dose of oxaliplatin of 458 ± 207 mg/m², allowing a mean cumulative exposure of 1,349 ± 249 mg/m². We identified no difference in oxaliplatin exposure prior to inclusion in the study between responders and nonresponders (957 ± 408 mg/m² versus 911 ± 213 mg/m², P = NS). In contrast, the beneficial effect of mangafodipir in responders allowed a mean additional exposure to oxaliplatin (510 ± 212 mg/m²) that was significantly higher than that in nonresponders (319 ± 113 mg/m², P = 0.039) (Figure 5C).

Effect of mangafodipir on oxidative stress in patients. We found that AOPPs determined before each cycle were lower in responders than in nonresponders (P = 0.027) (Figure 4C). Consistently, SOD levels were higher in responders than in nonresponders, suggesting an increased oxidative burst in nonresponders (P = 0.020) (Figure 4D). Further, we observed no differences in GR activities or plasma thiols (Figure 4, E and F).

This report shows the beneficial effect of mangafodipir’s association with oxaliplatin in terms of avoiding oxaliplatin-induced neurotoxicity in a mouse model and in patients with grade ≥2 oxaliplatin neuropathy. We believe that this finding may lead to a major breakthrough in the treatment of patients with oxaliplatin, since severe neurotoxicity is the main reason for dose reduction and discontinuation of oxaliplatin.

In order to test our hypothesis that mangafodipir is effective in treating the acute and chronic peripheral neuropathy induced by oxaliplatin, we designed a model of oxaliplatin-induced neurotoxicity in C57Bl/6 mice. All of the clinical and electrophysiological tests we conducted showed that mangafodipir effectively prevented the onset of locomotor and sensitivity disturbances and neuromuscular hyperexcitability in mice treated with oxaliplatin. Furthermore, morphological analyses revealed a decreased internodal (i.e., axonal and myelin sheath layers) diameter of the isolated myelinated nerve fibers in oxaliplatin-treated mice that was abrogated by oxaliplatin’s association with mangafodipir. This involvement of large fibers is a well-known characteristic of platinum-induced neurotoxicity, and our data are in agreement with the morphological changes observed by several groups (19).

The patterns we observed of excitability changes reflecting modulation in axonal membrane potential and ion channel function suggest the involvement of voltage-gated channels in this neuropathy. Previous data have suggested that these changes could result from the dysfunction of voltage-gated ion channels, since either persistent sodium channel activity or decreased potassium conductance can produce axonal hyperexcitability (20). Indeed, in the past decade, it has often been hypothesized that oxaliplatin-induced neuropathy results from defects in voltage-gated sodium channels, resulting in an increase in the amplitude and duration of action potentials that lengthen the refractory period of peripheral nerves (21–23). Nevertheless, Wilson et al. showed no benefit from the potent potassium channel blocker carbamazepine to prevent acute, reversible oxaliplatin-induced neuropathy (20). In vitro studies of various vertebrate nerves showed that dysfunction of voltage-gated potassium and/or sodium channels is involved in oxaliplatin-induced axonal hyperexcitability (7). Thus, the channels involved in the neuropathy secondary to oxaliplatin treatment had been ill defined until recent reports clearly implicated the voltage-gated potassium channels as targets of oxaliplatin, offering new insights into the pharmacological prevention of peripheral neuropathy (24–27). Our mouse model not only confirms the electrophysiological changes in potassium channels, but to the best of our knowledge, also demonstrates for the first time the therapeutic effect of mangafodipir.

Mice treated with oxaliplatin displayed an elevation in serum AOPPs that was probably representative of the pro-oxidative activity of the drug. Since AOPP levels were reduced in mice after 4 weeks of treatment with mangafodipir, we undertook to determine which step of the oxidative cascade was targeted by the molecule. Like mangafodipir, MnTBAP is a chelate of manganese with SOD-like activity, but unlike mangafodipir, it is devoid of vitamin B6 activity (16). Unlike vitamin B6, we found that MnTBAP prevented neuromuscular hyperexcitability, findings that are in accordance with those of Ang et al. following administration of vitamin B complex (28). Therefore, our own data suggest that mangafodipir prevents oxaliplatin-induced neuropathy by scavenging superoxide anions through its SOD-like activity.

Given the data obtained in our animal model, a phase II clinical trial was designed to investigate the curative effect of mangafodipir in patients treated with oxaliplatin. Burakgazi et al. (29) have shown that the two best means of evaluating the severity of oxaliplatin neuropathy are through the use of clinical criteria and the distal leg intraepidermal nerve fiber density assay. The latter was not appropriate for our study, since the patients had grade ≥2 neuropathy at the time of inclusion and very likely had diminished nerve fiber density at the start of the study. Moreover, responder patients in our study received oxaliplatin for 4 months at most, which is not a sufficient duration to expect any improvement in nerve fiber density. Therefore, we used clinical criteria to evaluate the severity of neuropathy.

We found that mangafodipir proved effective in stabilizing or improving grade ≥2 sensory neuropathy in 77% of patients who underwent 4 cycles of oxaliplatin-based chemotherapy. After 8 cycles of chemotherapy, 6 of 7 patients had grade ≤2 neuropathy.

With the addition of mangafodipir to oxaliplatin, the patients already exposed to a mean dose of 880 mg/m² were able to receive a mean additional dose of 458 mg/m² of oxaliplatin despite their preexisting neuropathy. The patients were able to continue receiving effective oxaliplatin therapy, resulting in a median progression-free survival of 2.75 months. Moreover, the addition of mangafodipir led to a median overall survival of 33.2 months. Thus, mangafodipir allows a major improvement in the use of oxaliplatin, since severe neurotoxicity is the main reason for dose reduction and discontinuation of oxaliplatin in patients who have a cumulative dose of 750 mg/m² or more (3, 30, 31).

Further, our data provide evidence that mangafodipir has both curative and preventative properties in oxaliplatin-induced neuropathy, and to the best of our knowledge, this is the first report of successful therapy for this disease.

These results, along with the significant increase observed in neutrophil cell counts with oxaliplatin treatment, are in agreement with previous reports from our team and others that mangafodipir can protect a variety of normal cells from oxidative stress, and in particular from the oxidative stress induced by oxaliplatin, without abrogating the drug’s anticancer effect (2, 16–18, 32, 33). Recently, Karlsson et al. confirmed our preclinical data in patients with regard to hematological protection, but were not able to obtain data regarding the prevention of neuropathy (34).

We found that plasma SOD–like activity was lower in nonresponder patients than in responder patients. Consistently, we observed that the mean serum AOPP concentration in nonresponders was higher, suggesting a more intensive antioxidative effect of mangafodipir in responders than in nonresponders. The nonresponders in our study were either insufficiently exposed to mangafodipir, or had already reached a chronic stage of the disease. Although these results are in line with those obtained in our animal model, they are not truly comparable. Indeed, the doses of oxaliplatin and mangafodipir administered to mice cannot be extrapolated to patients, and the frequency and sites of the mangafodipir injections were not the same. However, altogether, our data suggest that mangafodipir acts upon voltage-gated potassium channels through its antioxidant properties. Moreover, the serum levels of AOPPs could be used as a predictive marker of mangafodipir’s efficacy in preventing oxaliplatin-induced neuropathy.

Chronic exposure to manganese, which appears to be the active component of mangafodipir that prevents neuropathy, can paradoxically lead to neurological side effects, particularly Parkinson-like disease (35). The threshold of manganese toxicity in vivo is unknown, but the maximal increase in plasma concentration (25 nmol/l) reached in our patients was 4,000 times less than the toxic dose in vitro (36). This explains why we observed no clinical or biological side effects of mangafodipir during the trial.

In conclusion, mangafodipir is presently the only available drug that can prevent the worsening of — and that can even ameliorate — oxaliplatin-induced peripheral neuropathy, thus allowing the continuation of platinum-based chemotherapy. Therefore, mangafodipir should be considered a treatment option in patients with grade 2 oxaliplatin–induced neuropathy when oxaliplatin is considered effective against the cancer.

View Supplemental data

The authors are grateful to Agnes Colle for her excellent typing of the manuscript.

Address correspondence to: Frédéric Batteux, Laboratoire d’Immunologie, 24 rue du faubourg St. Jacques 75679 Paris cedex 14, France. Phone: 33.1.58.41.21.41; Fax: 33.1.58.41.20.08; E-mail: frederic.batteux@cch.aphp.fr.

Conflict of interest: Frédéric Batteux and Bernard Weill are co-founders of Protexel, a research and development company aiming to develop mangafodipir as a commercial drug. Frédéric Batteux and Bernard Weill are co-inventors of patents describing mangafodipir as a liver-protective and anticancer agent. They have received no income from Protexel.

Role of funding sources: The studies in the animal model were funded by the Université Paris Descartes and the Ministère de la Recherche et de l’Enseignement Supérieur. The clinical trial was funded by Assistance Publique-Hôpitaux de Paris.

Reference information: J Clin Invest. 2014;124(1):262–272. doi:10.1172/JCI68730.

See the related article at The search for treatments to reduce chemotherapy-induced peripheral neuropathy.

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