Peripheral neuropathy is a common and serious dose-limiting toxicity associated with taxane administration. BNP7787 (disodium 2,2’-dithio-bis-ethane sulfonate) has been developed as a novel chemoprotectant to prevent chemotherapy-induced neuropathy. In the present study, we investigated the neuroprotective effects of BNP7787 in rodent models of paclitaxel-induced neuropathy and potential molecular mechanism of action that may explain the observed neuroprotective effect. Repetitive intravenous injections of paclitaxel (6 mg/kg/day x 5, once every two days) induced thermal hypoalgesia and reduced nerve conduction velocity (NCV) in Wistar rats. The simultaneous intravenous injection of BNP7787 (1000 mg/kg/day x 5, once every two days) prevented the thermal hypoalgesia in the hind paw and reduction of NCV in tail vein of rats. We also observed that BNP7787 (2000 mg/kg/day x 5, once every week) inhibited the progression of mechanical hyperalgesia for tactile sense induced by the intraperitoneal injection of paclitaxel (12 mg/kg/day x 5, once every week) in rats. Moreover, it was observed that the pathological changes induced by paclitaxel (30 mg/kg/day x 3, once every two days) were mitigated by the concomitant injection of BNP7787 (2000 mg/kg x 3, once every two days) in sciatic and tibial nerves of BDF1 mice. At the same time, BNP7787 did not interfere with the anti-tumor effects of paclitaxel in in vivo and in vitro studies. Interestingly, the single intravenous injection of BNP7787 (2000 mg/kg) significantly increased the concentration of nerve growth factor (NGF) in plantar skin of mice within several hours, although BNP7787 administration did not change the concentrations of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We observed that treatment with BNP7787 increased the levels of NGF in the medium of a mouse fibroblast cell line (L-M cells). In conclusion, our results indicate that BNP7787 has a neuroprotective effect against paclitaxel-induced neuropathy and one of the potential mechanisms may involve increased secretion of NGF.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]