Abstract
Paclitaxel (Taxol®) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days −1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day −1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone.
Highlights
Paclitaxel is a taxane-derived chemotherapeutic used alone, or in combination therapy, for the treatment of ovarian, breast and advanced non-small cell lung cancers, and AIDS-related Kaposi’s sarcoma
Considering that mitochondria are a major source of reactive oxygen species (ROS) as a by-product of oxidative phosphorylation, we examined the potential causal role of ROS in chemotherapyinduced painful peripheral neuropathy
We have examined the role of ROS in the maintenance and development of paclitaxel-induced painful peripheral neuropathy in vivo
Summary
Paclitaxel is a taxane-derived chemotherapeutic used alone, or in combination therapy, for the treatment of ovarian, breast and advanced non-small cell lung cancers, and AIDS-related Kaposi’s sarcoma. Painful peripheral neuropathy is the major dose-limiting side-effect of paclitaxel therapy. Patients describe various sensory symptoms including mechanical allodynia, spontaneous pain, cold allodynia, numbness, tingling, in a ‘stocking and glove’ distribution [3,4,5]. Emergence of these symptoms can mean that patients cannot complete optimal chemotherapy schedules [6] potentially limiting anti-cancer actions. The incidence and severity of paclitaxel-induced pain symptoms correlates with increasing cumulative doses of paclitaxel [7,8]. There is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathy. Several analgesics with established efficacy in other painful neuropathies have failed to show any efficacy in double-blinded, placebo-controlled trials of patients with chemotherapy-induced painful peripheral neuropathy [10,11,12,13]
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