Development Of Paclitaxel-induced Peripheral Neuropathy Research Articles

Inhibitory Effect of α1 Receptor Antagonists on Paclitaxel-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

The anticancer drug, paclitaxel, is widely used for ovarian, breast, non-small cell lung, and gastric cancers; however, it induces peripheral neuropathy as a side effect. There is insufficient evidence-based prophylaxis, and new prophylaxis and treatment methods are required. We examined the effect of α1-receptor antagonists on paclitaxel-induced peripheral neuropathy using Sprague-Dawley rats and a large adverse event database. The repeated administration of doxazosin or tamsulosin significantly reduced the response threshold to paclitaxel administration in animal models. In the sciatic nerve tissue, axonal degeneration and myelopathy were significantly suppressed. Furthermore, an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database suggested that the group using α1 inhibitors showed a lower reporting rate for paclitaxel-related peripheral neuropathy than the group that did not use these inhibitors (odds ratio (95% confidence interval): tamsulosin 0.21 (0.08-0.56), p < 0.01, doxazosin 0.41 (0.10-1.65), p = 0.195; any α1 receptor antagonist 0.54 (0.38-0.76), p < 0.01). Thus, doxazosin and tamsulosin may inhibit the development of paclitaxel-induced peripheral neuropathy by suppressing neurodegeneration, particularly axonal degeneration and myelopathy.

ASSESSMENT OF EFFICIENCY OF ALPHA-LIPOIC ACID AND IPIDACRINE HYDROCHLORIDE TREATMENT FOR PREVENTION OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY USING THE EQ-5D 5L QUALITY OF LIFE QUESTIONNAIRE

Introduction. Paclitaxel is the most common chemotherapeutic agent from the taxane family, which is effective in treating many cancer types, including breast cancer. Despite the benefits of taxane-containing treatment regimens, patients develop neurosensory and neuromotor symptoms associated with the treatment, a condition known as chemotherapy-induced peripheral neuropathy.
 The aim of the study. To evaluate the efficacy of a combination of alpha-lipoic acid and acetylcholinesterase inhibitor ipidacrine hydrochloride to prevent the development of paclitaxel-induced peripheral neuropathy and improve its course in patients with breast cancer using the data of the EQ-5D 5L Quality of Life Questionnaire.
 Materials and methods. The study was conducted on 70 patients with breast cancer (T1-4N0-3M0-1), who were hospitalized at the Precarpathian Clinical Oncology Center of Ivano-Frankivsk Regional Council in 2014-2022. All patients received six cycles of chemotherapy according to the AT or ET regimens: paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion + doxorubicin 60 mg/m2 (AT), or paclitaxel at a similar dose + epirubicin 90 mg/m2 (ET) once in 3 weeks in neoadjuvant, adjuvant or palliative modes. Patients were randomized into two groups: patients of group I (n = 35) received polychemotherapy without the use of drugs for the prevention of neuropathy, and patients of group II (n = 35) received polychemotherapy and a preventive treatment of neuropathy. The scheme for the prevention of paclitaxel-induced peripheral neuropathy included a combination of alpha-lipoic acid with an acetylcholinesterase inhibitor ipidacrine hydrochloride. In order to assess the quality of life and effectiveness of the studied paclitaxel-induced peripheral neuropathy prevention regimen in patients with breast cancer, we have used the EQ-5D 5L quality of life questionnaire before and after the 3rd and 6th cycles of paclitaxel chemotherapy.
 Results. The study of breast cancer patients showed a statistically significant deterioration in all five aspects of quality of life included in the EQ-5D 5L quality of life questionnaire, which progressed with increasing cumulative dose of paclitaxel. In addition, the application of the study scheme for the prevention of paclitaxel-induced peripheral neuropathy in patients of group II, in contrast to patients of group I, led to a statistically significant improvement according to their answers to questions about pain or discomfort, both after 3 and after 6 cycles of chemotherapy with paclitaxel - by 14.09 % (p < 0.05) and 19.49 % (p < 0.01), respectively. According to the questionnaire data, after 6 cycles of chemotherapy self-care of patients of group II in contrast to patients of group I significantly improved (by 21.21 %, p < 0.05). Patients' answers to questions about the other three aspects of quality of life (mobility, normal daily activities, anxiety or depression) did not show a significant improvement in patients of group II, both after 3 and 6 cycles of paclitaxel chemotherapy. The mean value of the assessment of the general condition according to the visual-analog scale significantly improved after 3 and 6 cycles of chemotherapy with paclitaxel in patients of group II, in contrast to patients of group I - by 6.80 % (p < 0.001) and 13.40 % (p < 0.001), respectively.

69. Murphy Roths Large Mice Demonstrate Resistance to the Development of Paclitaxel-induced Peripheral Neuropathy

69. Murphy Roths Large Mice Demonstrate Resistance to the Development of Paclitaxel-induced Peripheral Neuropathy

Targeting interleukin-20 alleviates paclitaxel-induced peripheral neuropathy.

The role of immune mediators, including proinflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here, we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel upregulated IL-20 through dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.

Activation of KCNQ Channels Prevents Paclitaxel-Induced Peripheral Neuropathy and Associated Neuropathic Pain

Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain are the most common and serious adverse effects experienced by cancer patients receiving paclitaxel treatment. These effects adversely impact daily activities and consequently the quality of life, sometimes forcing the suspension of treatment and negatively influencing survival. Patients are usually at high risk of developing PIPN if paclitaxel induces acute pain, which strongly suggests that an acute increase in the excitability of nociceptors underlies the chronic alterations of PIPN. KCNQ/Kv7 channels are widely expressed in the primary sensory neurons to modulate their excitability. In the present study, we show that targeting KCNQ/Kv7 channels at an early stage is an effective strategy to attenuate the development of PIPN. We found that paclitaxel did not decrease the expression level of KCNQ/Kv7 channels in the primary sensory neurons as detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. However, retigabine, which is a specific KCNQ/Kv7 channel opener, attenuated significantly the development of PIPN, as shown by both morphologic and behavioral evidence. We also observed that retigabine had no obvious effect on the chemosensitivity of breast cancer cells to paclitaxel. Although retigabine has been approved by the FDA as an anticonvulsant, our study suggests that this drug can be repurposed to attenuate the development of PIPN. PerspectivePaclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. The results of our study demonstrated that retigabine (a clinically available medicine) can be used to attenuate the development of paclitaxel-induced peripheral neuropathy.

Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy.

Approximately 25% of breast cancer patients experience treatment delays or discontinuation due to paclitaxel-induced peripheral neuropathy (PN). Currently, there are no predictive biomarkers of PN. Pharmacometabolomics is an informative tool for biomarker discovery of drug toxicity. We conducted a secondary whole blood pharmacometabolomics analysis to assess the association between pretreatment metabolome, early treatment-induced metabolic changes, and the development of PN. Whole blood samples were collected pre-treatment (BL), just before the end of the first paclitaxel infusion (EOI), and 24 h after the first infusion (24H) from sixty patients with breast cancer receiving (80mg/m2) weekly treatment. Neuropathy was assessed at BL and prior to each infusion using the sensory subscale (CIPN8) of the EORTC CIPN20 questionnaire. Blood metabolites were quantified from 1-D-1H-nuclear magnetic resonance spectra using Chenomx® software. Metabolite concentrations were normalized in preparation for Pearson correlation and one-way repeated measures ANOVA with multiple comparisons corrected by false discovery rate (FDR). Pretreatment histidine, phenylalanine, and threonine concentrations were inversely associated with maximum change in CIPN8 (ΔCIPN8) (p < 0.02; FDR ≤ 25%). Paclitaxel caused a significant change in concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, pyruvate, o-acetylcarnitine, and several amino acids from BL to EOI and/or 24H (p < 0.05; FDR ≤ 25%), although these changes were not associated with ΔCIPN8. Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis.

Regulatable Transgene Expression for Prevention of Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication associated with drug treatment of cancer for which there are no effective strategies of prevention or treatment. In this study, we examined the effect of intermittent expression of neurotophin-3 (NT-3) or interleukin-10 (IL-10) from replication-defective herpes simplex virus (HSV)-based regulatable vectors delivered by subcutaneous inoculation to the dorsal root ganglion (DRG) on the development of paclitaxel-induced peripheral neuropathy. We constructed two different tetracycline (tet)-on-based regulatable HSV vectors, one expressing NT-3 and the other expressing IL-10, in which the transactivator expression in the tet-on system was under the control of HSV latency-associated promoter 2 (LAP-2), and expression of the transgene was controlled by doxycycline (DOX). We examined the therapeutic effect of intermittent expression of the transgene in animals with paclitaxel-induced peripheral neuropathy modeled by intraperitoneal injection of paclitaxel (16 mg/kg) once a week for 5 weeks. Intermittent expression of either NT-3 or IL-10 3 days before and 1 day after paclitaxel administration protected animals against paclitaxel-induced peripheral neuropathy over the course of 5 weeks. These results suggest the potential of regulatable vectors for prevention of chemotherapy-induced peripheral neuropathy.

Paclitaxel inhibits mRNA transport in axons

Paclitaxel is an integral component of solid tumor treatment. This chemotherapeutic agent provokes an often irreversible peripheral sensory neuropathy with pathological features of distal axonal degeneration. Current pathological concepts assume that polymerization of axonal microtubules and mitochondrial dysfunction contributes to the development of paclitaxel-induced peripheral neuropathy. The relationship, however, between microtubule stabilization, mitotoxicity and axonal degeneration is still not completely understood. To explore the function of axonal mitochondria we treated transgenic mice that harbor cyan fluorescent protein (CFP)-labeled neuronal mitochondria with repeated doses of paclitaxel and assessed neuropathic changes by nerve conduction and histological studies. In addition, mitochondrial content and morphology was determined by ex vivo imaging of axons containing CFP-labeled mitochondria. Using quantitative RT-PCR and fluorescence-labeled mRNA we determined axonal mRNA transport of nuclear encoded mitochondrial proteins. Prolonged treatment with high doses of paclitaxel-induced a predominant sensory neuropathy in mice. Although mitochondrial velocity in axons per se was not altered, we observed significant changes in mitochondrial morphology, suggesting that paclitaxel treatment impairs the dynamics of axonal mitochondria. These changes were caused by decreased levels of nuclear encoded mRNA, including the mitochondrial fusion/fission machinery. Moreover, impaired axonal mRNA transport in vitro resulted in mitochondrial dysfunction and subsequent axonal degeneration. Taken together, our experiments provide evidence that disrupted axonal transport of nuclear derived mRNA plays a crucial role in the pathogenesis of paclitaxel-induced sensory neuropathy.

Association of paclitaxel-induced sensory peripheral neuropathy with the ABCB1 genetic variant and age.

11100 Background: The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by the age and genetic composition of patients. Paclitaxel is known to act as a substrate in SLCO1...

(384) Targeting KCNQ channels to prevent and ameliorate paclitaxel-induced peripheral neuropathy

Paclitaxel is routinely used to treat breast cancer patients. However, paclitaxel induces toxic effects, among which peripheral sensory neuropathy accompanied by neuropathic pain is particularly severe and is often a limiting factor in treatment. Several pharmacological interventions have been proposed for paclitaxel-induced chronic pain treatment, but none have been shown to be both widely effective and without serious side effects. Recent studies indicated that the development and maintenance of peripheral neuropathy including associated pain is driven by intense, long-lasting excitation of neurons exposed to paclitaxel. Reducing this excessive excitation may reverse or prevent paclitaxel-induced peripheral neuropathy. K+ channels (Kv7 or KCNQ/M channels) are abundantly expressed in primary sensory neurons to control excitability. We hypothesized that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN by reducing the hyperexcitability of primary sensory neurons. Retigabine, a specific opener of KCNQ channels, was used to test if increasing KCNQ channel activity would reverse or prevent paclitaxel-induced peripheral neuropathy including associated neuropathic pain. Paclitaxel was delivered to tumor-free adult rats and then retigabine was applied to paclitaxel-treated rats 2 weeks later to determine whether retigabine can attenuate established chronic neuropathic pain. Remarkably, retigabine significantly attenuated mechanical hypersensitivity induced by paclitaxel. We also applied retigabine for 10 days during paclitaxel treatment to see if it reduces the development of paclitaxel-induced peripheral neuropathy (PIPN) and associated pain. Retigabine plus paclitaxel treatment resulted in significantly higher mechanical thresholds compared to vehicle plus paclitaxel treatment, assessed 2 weeks after the end of combined treatment. Furthermore, IENF density was reduced by 50% in rats that had received vehicle plus paclitaxel compared to rats co-treated with retigabine and paclitaxel. Our data suggest that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN. Paclitaxel is routinely used to treat breast cancer patients. However, paclitaxel induces toxic effects, among which peripheral sensory neuropathy accompanied by neuropathic pain is particularly severe and is often a limiting factor in treatment. Several pharmacological interventions have been proposed for paclitaxel-induced chronic pain treatment, but none have been shown to be both widely effective and without serious side effects. Recent studies indicated that the development and maintenance of peripheral neuropathy including associated pain is driven by intense, long-lasting excitation of neurons exposed to paclitaxel. Reducing this excessive excitation may reverse or prevent paclitaxel-induced peripheral neuropathy. K+ channels (Kv7 or KCNQ/M channels) are abundantly expressed in primary sensory neurons to control excitability. We hypothesized that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN by reducing the hyperexcitability of primary sensory neurons. Retigabine, a specific opener of KCNQ channels, was used to test if increasing KCNQ channel activity would reverse or prevent paclitaxel-induced peripheral neuropathy including associated neuropathic pain. Paclitaxel was delivered to tumor-free adult rats and then retigabine was applied to paclitaxel-treated rats 2 weeks later to determine whether retigabine can attenuate established chronic neuropathic pain. Remarkably, retigabine significantly attenuated mechanical hypersensitivity induced by paclitaxel. We also applied retigabine for 10 days during paclitaxel treatment to see if it reduces the development of paclitaxel-induced peripheral neuropathy (PIPN) and associated pain. Retigabine plus paclitaxel treatment resulted in significantly higher mechanical thresholds compared to vehicle plus paclitaxel treatment, assessed 2 weeks after the end of combined treatment. Furthermore, IENF density was reduced by 50% in rats that had received vehicle plus paclitaxel compared to rats co-treated with retigabine and paclitaxel. Our data suggest that KCNQ/Kv7 channels are a potential therapeutic target to ameliorate and prevent neuropathic pain associated with PIPN.

Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy

The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C8*3 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics. Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET™ Plus chip. Patients who carried the CYP2C8*2, *3, or *4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN. 412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR = 1.722, p = 0.018); however, the influences of the *2 and *4 SNPs were not independently significant (*2: p = 0.847, *4: p = 0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p = 0.0008) but not in the non-Caucasian replication group (p = 0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN. The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C8*3.

Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells

Spinal glial activation contributes to the development and maintenance of chronic pain states, including neuropathic pain of diverse etiologies. Cannabinoid compounds have shown antinociceptive properties in a variety of neuropathic pain models and are emerging as a promising class of drugs to treat neuropathic pain. Thus, the effects of repeated treatment with WIN 55,212-2, a synthetic cannabinoid agonist, were examined throughout the development of paclitaxel-induced peripheral neuropathy. Painful neuropathy was induced in male Wistar rats by intraperitoneal (i.p.) administration of paclitaxel (1mg/kg) on four alternate days. Paclitaxel-treated animals received WIN 55,212-2 (1mg/kg, i.p.) or minocycline (15mg/kg, i.p.), a microglial inhibitor, daily for 14days, simultaneous with the antineoplastic. The development of hypersensitive behaviors was assessed on days 1, 7, 14, 21 and 28 following the initial administration of drugs. Both the activation of glial cells (microglia and astrocytes) at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Similar to minocycline, repeated administration of WIN 55,212-2 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel-treated rats. WIN 55,212-2 treatment also prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatory cytokines (interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α). Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of WIN 55,212-2, probably via glial cells reactivity inactivation, on the development of this neuropathy.