Vincristine-induced peripheral neurotoxicity: A prospective cohort

Nama, Nassr; Barker, Mikaela K; Kwan, Celia; Sabarre, Cheryl; Solimano, Veronica; Rankin, Anne; Raabe, Jennifer; Ross, Colin J.D.; Carleton, Bruce; Zwicker, Jill G.; Rassekh, Shahrad R.

doi:10.1080/08880018.2019.1677832

Cited by 23 publications

(12 citation statements)

References 45 publications

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“…The main side effect of vincristine is a peripheral neuropathy characterized by motoric, autonomic, and sensory symptoms, such as gait abnormalities, obstipation, or changes in the perception of mechanical or vibration stimuli ( Mora et al, 2016 ; Starobova and Vetter, 2017 ). Vincristine-induced peripheral neuropathy (VIPN) is thus a serious dose-limiting side effect contributing to morbidity and reduced quality of life in patients treated with vincristine ( Kautio et al, 2011 ; Nama et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release

Starobova

Monteleone

Adolphe

et al. 2021

Journal of Experimental Medicine

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Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.

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Section: Introductionmentioning

confidence: 99%

Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release

Starobova

Monteleone

Adolphe

et al. 2021

Journal of Experimental Medicine

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“…5,6 Vincristine has been known to induce microtubule destabilisation and deficits in axonal transport, and thus, has more neurotoxicity than other vinca alkaloid agents. 7,8 Nefopam has drawn interest for its antinociceptive and antihyperalgesic effects; it acts by influencing monoamines, and the noradrenergic and/or serotonergic system, resulting in the prevention and reduction of central neural sensitisation. [9][10][11] In a study with spinal nerve ligation models, intrathecal nefopam produced an antiallodynic effect by inhibition of microglial and astrocytic activation, which are reportedly involved in the release of nociceptive mediators and facilitation of the pain process pathway.…”

Section: Introductionmentioning

confidence: 99%

<p>The Antiallodynic Effect of Nefopam on Vincristine-Induced Neuropathy in Mice</p>

Lee

Sim

Cho

et al. 2020

JPR

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Background: Chemotherapy-induced neuropathic pain is a disabling condition following cancer treatment. Vincristine has more neurotoxicity than other vinca alkaloid agents. This study evaluated the correlation of different doses of nefopam with antiallodynic effects in a mouse vincristine neuropathy model. Methods: A peripheral neuropathic mouse model was made by intraperitoneal injection of vincristine (0.1 mg/kg/day; 5-day-on, 2-day-off schedule over 12 days). After the development of allodynia, mice were injected intraperitoneally with 0.9% normal saline (NS group) or various doses (10, 30, 60 mg/kg) of nefopam (Nefopam group). We examined allodynia using von Frey hairs pre-administration and at 30, 60, 90, 120, 180, 240 mins, and 24 hrs after drug administration. We also measured the neurokinin-1 receptor concentrations in the spinal cord to confirm the antiallodynic effect of nefopam after drug administration. Results: The peripheral neuropathic mouse model showed prominent mechanical allodynia. Intraperitoneal nefopam produced a clear dose-dependent increase in paw withdrawal threshold compared with pre-administration values and versus the NS group. The concentration of neurokinin-1 receptor was significantly decreased in the Nefopam group (P<0.05). Conclusion: Intraperitoneally administered nefopam yielded a dose-dependent attenuation of mechanical allodynia and decreased neurokinin-1 receptor concentration, suggesting that the neurokinin-1 receptor is involved in the antiallodynic effects of nefopam in vincristine neuropathy.

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“…The incidence of myelosuppression was 51% [47]. Grade III anaemia and a decrease in CD4+ lymphocytes were also noticed [32] and neurotoxicity caused by vincristine also observed [49]. A skin rash also occurred [31,35].…”

Section: Introduction and Objectivementioning

confidence: 94%