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Evaluation of pre‐existing neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model

Pre‐existing neuropathy, a not uncommon feature in oncologic patients, is a potential but non‐confirmed risk factor to develop early or severe chemotherapy‐induced neuropathy. The main goal of this study is to evaluate the role of pre‐existing neuropathy induced by vincristine (VNC) or bortezomib (BTZ) as a risk factor to develop more severe BTZ‐induced neuropathy in a mouse model. VNC, at doses of 1 and 1.5 mg/kg given twice per week for 4 weeks, induced a moderate and severe sensory‐motor neuropathy, primarily axonal, with predominant involvement of myelinated sensory axons. The neuropathy induced by BTZ at dose of 1 mg/kg given twice per week for 6 weeks was a mild axonal sensory neuropathy involving myelinated and unmyelinated fibers. The neuropathy in mice previously treated and retreated with the same schedule of BTZ after 4 weeks of washout period was similar in profile and severity to the one observed after the first treatment. When basal neuropathy was classified as moderate (most of BTZ‐treated animals) or severe (all VNC‐treated animals and two BTZ‐treated animals), there was a more marked decline in sensory nerve function during BTZ retreatment in the group with basal severe neuropathy (−86%) than in the groups with basal mild (−57%) or without neuropathy (−52%; p < 0.001). Histopathological findings supported the functional results. Therefore, this study shows that the presence of a severe neuropathy previous to treatment with an antitumoral agent, such as BTZ, results in a more marked involvement of peripheral nerves.