Abstract
Vincristine is an antineoplastic substance that is part of many chemotherapy regimens, used especially for the treatment of a variety of pediatric cancers including leukemias and brain tumors. Unfortunately, many vincristine-treated patients develop peripheral neuropathy, a side effect characterized by sensory, motoric, and autonomic symptoms. The sensory symptoms include pain, in particular hypersensitivity to light touch, as well as loss of sensory discrimination to detect vibration and touch. The symptoms of vincristine-induced neuropathy are only poorly controlled by currently available analgesics and therefore often necessitate dose reductions or even cessation of treatment. The aim of this study was to identify new therapeutic targets for the treatment of vincristine-induced peripheral neuropathy (VIPN) by combining behavioral experiments, histology, and pharmacology after vincristine treatment. Local intraplantar injection of vincristine into the hind paw caused dose- and time-dependent mechanical hypersensitivity that developed into mechanical hyposensitivity at high doses, and lead to a pronounced, dose-dependent infiltration of immune cells at the site of injection. Importantly, administration of minocycline effectively prevented the development of mechanical hypersensitivity and infiltration of immune cells in mouse models of vincristine induce peripheral neuropathy (VIPN) based on intraperitoneal or intraplantar administration of vincristine. Similarly, Toll-like receptor 4 knockout mice showed diminished vincristine-induced mechanical hypersensitivity and immune cell infiltration, while treatment with the anti-inflammatory meloxicam had no effect. These results provide evidence for the involvement of Toll-like receptor 4 in the development of VIPN and suggest that minocycline and/or direct Toll-like receptor 4 antagonists may be an effective preventative treatment for patients receiving vincristine.
Highlights
Vincristine is part of many chemotherapy regimens and one of the most important antineoplastics for the treatment of a range of pediatric malignancies including medulloblastomas and neuroblastomas
Mouse models based on systemic administration of vincristine induce symptoms of mechanical allodynia, but poorly replicate important symptoms of human neuropathy such as sensory loss or gait disturbances
We sought to isolate the dosedependent actions of vincristine on peripheral sensory neurons, we established a mouse model of vincristineinduced peripheral neuropathy (VIPN) based on the local administration of vincristine (1 pg, 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 μg, and 10 μg) via shallow subcutaneous injections into the hind paw of C57BL/6J mice (Figure 1)
Summary
Vincristine is part of many chemotherapy regimens and one of the most important antineoplastics for the treatment of a range of pediatric malignancies including medulloblastomas and neuroblastomas. Most patients receiving vincristine develop a dose-dependent peripheral neuropathy characterized by sensory, motoric, and autonomic disturbances (Ramchandren et al, 2009; Toopchizadeh et al, 2009; Seretny et al, 2014; Lavoie Smith et al, 2015). Despite the wide range of analgesic and neuromodulatory treatments available, none successfully control vincristine-induced pain, leading to further reduction in the quality of life of vincristine-treated patients, as well as dose reduction or cessation of the anticancer therapy (Lavoie Smith et al, 2013). Vincristine is known to cause dysregulation and structural modifications of neuronal mitochondria, leading to activation of apoptotic pathways, alteration in neuronal excitability, and dysfunction of glial cells (Starobova and Vetter, 2017). Systemic administration of vincristine is associated with an inflammatory response, including the expression of integrins, and enhanced chemotaxis of immune cells (Kiguchi et al, 2009; Old et al, 2014)
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