Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms?

Oxaliplatin is a first‐line treatment for colorectal cancer. However, shortly following treatment, cold‐evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin‐induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy‐induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water (“cold hypersensitivity”) was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin‐induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin‐treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin‐induced peripheral neuropathy.

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“…It is likely that a persistent cold hypersensitivity would appear after further infusions (Carozzi et al. 2015). …”

Section: Discussionmentioning

confidence: 99%

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Shidahara

Ogawa

Nakamura

et al. 2016

Pharmacology Res & Perspec

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“…Previous investigators suggested that apoptosis plays an important role in paclitaxel toxicity. Paclitaxel stabilizes microtubules leading to cellular mitosis arrest and hence cell death (apoptosis) [34] . Microtubule stability affects axonal transport of growth factors leading to abnormal nerve physiology and loss of axonal integrity [7] .…”

Section: Discussionmentioning

confidence: 99%

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

Kassab

Elkaliny

2017

Egyptian Journal of Histology

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Background: Paclitaxel is a neurotoxic chemotherapeutic agent. The sensorimotor peripheral neuropathy is a serious dose limiting complication of paclitaxel therapy. Propolis is a natural honeybee product collected from plants. It has broad biological and pharmacological activities and a proposed neuroprotective role. Aim: To assess the possible protective role of propolis on paclitaxel-induced peripheral neuropathy in rat's sciatic nerve. Material and Methods: Twenty-four adult male albino rats were divided into four equal groups; control group, propolistreated group (50 mg/kg orally once daily), paclitaxel -treated group (16 mg/kg intraperitoneally once a week), and both paclitaxel & propolis-treated group. Animals were treated for 5 consecutive weeks. Specimens of sciatic nerve were processed for histological study by light and electron microscopy. Immunohistochemical study was carried out using CD68 antibody. Morphometric study and statistical analysis of light microscopic data were performed for all groups. Results: Compared to the control group, the sciatic nerve specimens of the paclitaxel-treated rats showed splitting of myelin lamellae with infolded myelin loops, together with invagination and evagination of the myelin sheath. Changes in the axons included formation of myelin figures, compression and irregularity. Schwann cells showed cytoplasmic vacuolation and dilated rER. Immunohistochemical study revealed a significant increase in the number of CD68 positive cells. On the other hand, minimal changes were observed in rats treated concomitantly with both paclitaxel and propolis, with a non-significant increase in CD68 positive cells. Conclusion: Paclitaxel induced structural changes in the myelinated fibers of sciatic nerve of albino rats. The concomitant treatment with propolis ameliorated these changes.

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“…However, CIPN is one of the most common dose-limiting adverse drug reactions (15)(16)(17). CIPN usually affects the dorsal root ganglia of primary sensory neurons.…”

Section: Discussionmentioning

confidence: 99%

A prospective study to evaluate the efficacy and safety of oral acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy

Sun

Shu

Liu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to evaluate the efficacy and safety of acetyl-L-carnitine (ALC) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). The study was carried out as a prospective, randomized, double-blind, placebo-controlled and paralleled clinical study. A total of 239 patients with CIPN were selected as the study subjects. Of the 239 subjects, 118 subjects received 3 g/day ALC orally for 8 weeks and 121 received a placebo. The primary endpoint was improvement of peripheral neuropathy by at least one grade. Patient status was assessed at week 4, 8 and 12 after enrollment into the study. In both the full analysis set (FAS) and the per-protocol set (PPS), peripheral sensory neuropathy was significantly ameliorated in the ALC group with 50.5 and 51.6% patients meeting the primary endpoint at week 8, compared with 24.1 and 23.1% of patients in the placebo group (P<0.001 in both sets). Secondary endpoints, such as the nerve electrophysiological examination and the Karnofsky physical score were also significantly improved in patients receiving ALC treatment, as compared with the placebo group (FAS, P= 0.0463 and P= 0.022; PPS, P= 0.0076 and P= 0.0064, respectively). Cancer-associated fatigue was significantly alleviated following ALC treatment in the PPS (P= 0.0135). In the safety analysis set, the difference in adverse events incidence between the two groups was not statistically significant (P= 0.3903). There were only two severe adverse events in the ALC group, which were not associated with the effect of ALC. In conclusion, the results of the present study demonstrated that in Chinese patients with cancer, oral administration of ALC is effective at ameliorating peripheral sensory neuropathy induced by chemotherapy, as well as reducing of cancer-associated fatigue and improving physical conditions.

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Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms?

Cited by 362 publications

References 197 publications

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

A prospective study to evaluate the efficacy and safety of oral acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy

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