Calcium channel blockers reduce oxaliplatin-induced acute neuropathy: a retrospective study of 69 male patients receiving modified FOLFOX6 therapy.

Oxaliplatin-based chemotherapy has been widely used for colorectal cancer. However, it causes severe acute and chronic peripheral neuropathies. Recently, we reported that calcium channel blockers prevent the oxaliplatin-induced cold hyperalgesia in rats. The purpose of this study was to determine whether the treatment with calcium channel blockers prevents the peripheral neuropathy during oxaliplatin therapy. The electronic medical charts for patients who received modified FOLFOX6 regimen from January 2008 to December 2010 were evaluated. Of the 200 patients who received modified FOLFOX6 therapy, 84 patients were excluded due to the exclusion criteria. Calcium channel blockers had been taken by 26 of 69 male patients, but only three of 47 female patients. Therefore, in the present analysis, the male data of the groups with and without calcium channel blockers (n=26 and 43, respectively) were compared. The cumulative incidence curve of acute neuropathy was significantly lower in the group with calcium channel blockers (P=0.0438, log-rank test), whereas there was no difference between these groups in the cumulative incidence curve of chronic neuropathy (P=0.4919, log-rank test). The present study indicated that calcium channel blockers inhibit the development of acute peripheral neuropathy in patients receiving modified FOLFOX6 therapy.

Pemirolast reduces cisplatin-induced kaolin intake in rats.

Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

Involvement of substance P in peripheral neuropathy induced by paclitaxel but not oxaliplatin.

The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. In von Frey and acetone tests in rats repeated administration of paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both mechanical allodynia and cold hyperalgesia. Paclitaxel-induced peripheral neuropathy was reversed primarily by the acute administration of pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 µg/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-indole (GR159897), 100 µg/body i.t.] strongly reversed paclitaxel-induced neuropathy. On the other hand, oxaliplatin-induced peripheral neuropathy was not reversed by pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin.