Prevention Of Oxaliplatin-induced Neuropathy Research Articles

Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.

A phase Ib adaptive study of dasatinib for the prevention of oxaliplatin-induced neuropathy in patients with metastatic colorectal cancer receiving FOLFOX chemotherapy and bevacizumab.

TPS12125 Background: Neurotoxicity is one of the most significant and disabling side effects of oxaliplatin and frequently limits the cumulative amount that can be used. The mechanism of oxaliplatin-induced neurotoxicity remains uncertain, although our preliminary studies suggest that oxaliplatin uptake by organic cation transporter 2 (OCT2) into mouse and rat dorsal root ganglion is a prerequisite for oxaliplatin-induced peripheral neuropathy. The activity of OCT2 is dependent on tyrosine phosphorylation by the SRC-kinase family member Yes1, which is highly sensitive to inhibition by several FDA-approved, small molecule kinase inhibitors such as dasatinib. We have previously shown that pre-treatment with oral dasatinib prevented acute and chronic oxaliplatin-induced peripheral neuropathy in mouse and rat models. Methods: This is a phase Ib dose-finding study of dasatinib given in combination with mFOLFOX6 with or without bevacizumab. The study explores the hypothesis that the addition of dasatinib prior to oxaliplatin will inhibit OCT2 activity and reduce oxaliplatin-induced neuropathy. This hypothesis will be tested in a Bayesian Phase 1b trial with adaptive dose selection using efficacy-toxicity trade-offs (modified toxicity-efficacy probability interval dose-finding design) in patients with confirmed stage IV colorectal cancer who are candidates for mFOLFOX6 with bevacizumab therapy. Patients who have documented peripheral neuropathy or prior exposure to oxaliplatin will be excluded. The primary objective is to determine the recommended Phase 2 dose which is defined as the lowest intermittent dose of dasatinib that affects serum biomarkers of OCT2, including methylnicotinamide and creatinine, by ≥2-fold without influencing the clearance of oxaliplatin by > 20%. The following doses will be used: oxaliplatin 85mg/m2 IV, 5FU bolus 400mg/m2 IV bolus with Leucovorin 400mg/m2, bevacizumab 5mg/kg, followed by infusional 5FU 2400mg/m2 IV over 46 hours given on a day 1 and 15 schedule every 28 days. Dasatinib will be administered at one of 2 dose levels – 100mg or 140mg po. Dasatinib will be given 24 hours and 30 mins prior to oxaliplatin on C1D14, C1D15 respectively and repeated on C1D28 and C2D1. Secondary objectives include evaluation of the influence of dasatinib on the pharmacokinetics of oxaliplatin and vice versa. Quality of life will be explored using the CIPN20 questionnaire. The trial opened to enrollment in Dec 2019 (NCT04164069) and is accepting patients. Clinical trial information: NCT04164069 .

Abstract 5260: Prevention of oxaliplatin-induced neuropathy by using minocycline as a chemoprotectant: demonstration by imaging and behavioral assessment

Abstract Purpose: To utilize neurography, a novel imaging method based on retrograde transport of a molecular nerve imaging tracer, to assess the protective effect of minocycline on the development of Oxaliplatin-induced neuropathy. Materials and Methods: Female BALB/c mice received one of four treatments vehicle/vehicle, vehicle/minocycline, Oxaliplatin/vehicle, or Oxaliplatin/minocycline (n = 8/group). A 30 mg/kg cumulative dose of Oxaliplatin or dextrose vehicle was given in 10 divided intra-peritoneal doses across 3 weeks using two 5 days cycles. Animals were treated daily with 50 mg/kg minocycline or 0.9% saline vehicle by oral gavage beginning 48 h prior to the first Oxaliplatin treatment. Both imaging and behavioral data were collected at baseline and weekly for 3 weeks. For each imaging session, animals received fluorescently labeled TTc-Alexa790 (15 ug/20 uL) via intramuscular injection into the calf muscles. Fluorescent imaging (Xenogen IVIS 200) was used to image the distribution of TTc over 60 minutes, with ROI measurements taken over the lumbo-thoracic junction of the spine to quantitate fluorescent uptake. Neurobehavioral assessment for mechanical sensitivity was assessed through the use of von Frey nylon filaments to exert calibrated force on the footpads. The 50% hind paw withdrawal threshold was calculated. Results: Oxaliplatin/vehicle treated animals showed a significant decrease in transport of TTc during the second week of treatment (F (1,12) = 39.604, p<0.001), while the TTc transport of the vehicle/vehicle and oxaliplatin/minocycline remained stable across the experiment. The vehicle/minocycline group saw an increase in transport of TTc during the second week of treatments (F (1,12) = 42.533, p<0.001). Behavioral data indicated that Oxaliplatin treatment resulted in increased mechanical sensitivity, while minocycline treatment abrogated this effect, such that animals in the Oxaliplatin/vehicle group showed increased sensitivity compared to all other groups. This effect emerged within the first week of treatment and remained throughout the study. A linear correlation between paw withdrawal threshold and TTc transport at week 3 was found, with r = 0.7939, p<0.01, such that subjects with reduced TTc transport also displayed reduced mechanical thresholds. Conclusion: Oxaliplatin causes a decrease in retrograde axonal transport, and this reduction in transport correlates with neurobehavioral impairment due to neuropathy. We show that this effect can be attenuated by a chemo-protectant, minocycline, and that the protectant effect was apparent with both behavioral and imaging readouts. This suggests that minocycline can prevent the neuropathy induced by Oxaliplatin and that the mechanism of both the pathological effect and its prevention are related to retrograde axonal transport. Citation Format: Dawid Schellingerhout, Elizabeth Vichaya, Leo G. Flores, Daniela Ramos, Lucia Le Roux. Prevention of oxaliplatin-induced neuropathy by using minocycline as a chemoprotectant: demonstration by imaging and behavioral assessment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5260.