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Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia.

BackgroundOxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.ResultsAn increase of CaMKII phosphorylation was found in the spinal cord (L4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.ConclusionsThese results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.

BackgroundOxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells.MethodsOxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves.ResultsRepeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.ConclusionThese results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.

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Paclitaxel (Taxol ® ), an anticancer agent with a tubulinstabilizing action, is one of the key drugs in the treatment of breast cancer, ovarian cancer, and other solid tumors. Since standard paclitaxel is a highly hydrophobic agent, available products are dissolved in polyethylated castor oil (Cremophor EL ® ) and ethanol. Recently, nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane ® ), a novel solvent-free formulation of paclitaxel, has been approved in many countries. Nab-paclitaxel has several practical advantages over solvent-based paclitaxel, including a higher administration dose of paclitaxel (175 -210 to 260 mg/m 2 ), better transportability to tumor, shorter infusion time (3 h to 30 min) and no need for premedications for hypersensitivity reactions. In a Phase III trial, nab-paclitaxel exhibited a higher response and longer time to tumor progression compared with solvent-based paclitaxel in patients with metastatic breast cancer (1). On the other hand, in this trial, patients treated with nab-paclitaxel had a lower rate of neutropenia but a higher rate of sensory neuropathy (1). We previously reported that repeated administration of paclitaxel induced pain behaviors in rats (2, 3). However, the effects of nab-paclitaxel on the pain behaviors have not been studied. In this study, therefore, we compared the effects of nab-paclitaxel and standard paclitaxel on pain behaviors in rats.Male Sprague-Dawley rats (Kyudo Co., Tosu) were used for the peripheral neuropathy model. Rats were housed in groups of four to five per cage, with lights on from 7:00 AM to 7:00 PM. Animals had free access to food and water in their home cages. The experimental procedures were approved by the Committee for the Care and Use of Laboratory Animals at the Faculty of Medicine, Kyushu University.Paclitaxel (Taxol ® , 6 mg/mL in cremophor EL / ethanol 1:1) and nab-paclitaxel (Abraxane ® ) were obtained from Bristol-Myers Squibb Co. (Tokyo) and Taiho Pharmaceutical Co., Ltd. (Tokyo), respectively. Nabpaclitaxel was dissolved in saline. Paclitaxel (6 mg/kg), nab-paclitaxel (6 or 7.4 mg/kg), or saline was injected intravenously (i.v.) once a week for 4 weeks (on days 1, 8, 15, and 22). The dose of paclitaxel was chosen according to the previous reports (2, 3). Since the clinical dose of nab-paclitaxel is 23.8% higher than that of standard paclitaxel [nab-paclitaxel: 260 mg/m 2 (body surface area) and paclitaxel: 210 mg/m 2 (body surface area)], the doses of nab-paclitaxel were chosen to be 7.4 mg/kg (the 23.8% higher dose).We investigated the effects of nab-paclitaxel and standard paclitaxel on mechanical and cold allodynia in the von Frey and acetone tests. These tests were performed before the first drug administration (day 0) and *Corresponding author. n-egashi@pharm.med.kyushu-u.ac.jp Published online in J-STAGE on September 7, 2011 (in advance) doi: 10.1254/jphs.11062SC Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan Received April 5, 2011; Accepted July 26, 2011 Abs...

Hypersensitivity reactions, including anaphylaxis, are common side effects associated with docetaxel treatment in breast cancer patients. However, preventive measures have not yet been established. In this study, we retrospectively analyzed the risk factors for developing anaphylaxis in 182 female breast cancer patients treated with docetaxel. We found that 6.6% of all patients (n 12) experienced anaphylaxis. Multivariate analyses indicated that concentration of docetaxel higher than 0.275 mg/m 2 /mL, docetaxel dose rate higher than 1.15 mg/m 2 /min, and white blood cell count less than 4290 cells/mL are risk factors for developing docetaxel-related anaphylaxis. In particular, concentrations of docetaxel or doses per administration time were associated with a high odds ratio (11.88 or 11.60) for docetaxel-related anaphylaxis. Moreover, patients receiving doses in 250 mL volume experienced anaphylaxis more frequently than those receiving doses in 500 mL (7.0 vs. 0.9%, p 0.0236). Additionally, patients receiving treatments over 60 min tended to experience anaphylaxis more frequently than those who were treated over 90 min (6.7 vs. 1.1%, p 0.0637). The present results indicate that high docetaxel concentrations, high dose rates, and low white blood cell counts are risk factors for developing docetaxel-related anaphylaxis, and administering docetaxel diluted in 500 mL over 90 min may limit docetaxel-induced hypersensitivity reactions.

Oxaliplatin (L‐OHP) is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. We reported that NMDA receptors in spinal cord is involved in mechanical allodynia induced by L‐OHP (4 mg/kg, i.p., twice a week). In this study, we investigated the involvement of spinal glutamate in L‐OHP‐induced mechanical allodynia more closely. The L‐OHP‐induced mechanical allodynia was reversed not only by a NMDA receptor antagonist MK‐801 but also by an AMPA receptor antagonist NBQX. In vivo microdialysis, formalin‐induced nociception (5% formalin, 50µL, s.c.) sustainably increased extracellular glutamate concentration in the spinal cord in L‐OHP‐treated rats compared to vehicle‐treated rats, whereas tactile stimuli (brushing stimulation) increased extracellular glutamate concentration in the spinal cord in L‐OHP‐treated rats alone. Moreover, GLT‐1 (Glutamate transporter 1) but not GLAST (Glial glutamate transporter) and EAAC1 (Excitatory amino‐acid carrier 1), was decreased in the spinal cord dorsal horn in L‐OHP‐treated rats. These results suggest that L‐OHP inhibits uptake of extracellular glutamate by down‐regulation of GLT‐1 expression and increased accumulation of glutamate in the spinal cord.