Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice

Abstract

Chemotherapy-induced neurotoxicity is a significant problem associated with successful treatment of many cancers. Tubulin is a well-established target of antineoplastic therapy; however, tubulin-targeting agents, such as paclitaxel and the newer epothilones, induce significant neurotoxicity. Eribulin mesylate, a novel microtubuletargeting analogue of the marine natural product halichondrin B, has recently shown antineoplastic activity, with relatively low incidence and severity of neuropathy, in metastatic breast cancer patients. The mechanism of chemotherapy-induced neuropathy is not well understood. One of the main underlying reasons is incomplete characterization of pathology of peripheral nerves from treated subjects, either from patients or preclinically from animals. The current study was conducted to directly compare, in mice, the neuropathy-inducing propensity of three drugs: paclitaxel, ixabepilone, and eribulin mesylate. Because these drugs have different potencies and pharmacokinetics, we compared them on the basis of a maximum tolerated dose (MTD). Effects of each drug on caudal and digital nerve conduction velocity, nerve amplitude, and sciatic nerve and dorsal root ganglion morphology at 0.25 Â MTD, 0.5 Â MTD, 0.75 Â MTD, and MTD were compared. Paclitaxel and ixabepilone, at their respective MTDs, produced significant deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes, as well as moderate to severe degenerative pathologic changes in dorsal root ganglia and sciatic nerve. In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. Overall, our findings indicate that eribulin mesylate induces less neuropathy in mice than paclitaxel or ixabepilone at equivalent MTD-based doses. Cancer Res; 71(11); 3952-62. Ó2011 AACR.

Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs

“…For example, in mice treated for 2 weeks with the MTDs of the microtubule surface-binding drugs paclitaxel or ixabepilone, Wozniak and colleagues (12) observed significantly greater decreases in caudal and digital nerve conduction velocity and amplitude than were induced by the microtubule end-binding drug eribulin. The slight changes in nerve conduction velocity induced by eribulin were accompanied by less axonopathy in the sciatic nerve and less cellular damage in dorsal root ganglia as compared with paclitaxel or ixabepilone (12). This finding closely correlates with the clinical incidence of peripheral neuropathy with the three drugs, with paclitaxel and ixabepilone inducing a higher incidence of neuropathy in patients than eribulin (13)(14)(15)(16).…”

“…Paclitaxel (LC Laboratories) or eribulin was administered intravenously as three injections every other day for 2 weeks with a 2 day rest between weekly cycles at 30 mg/kg and 1.75 mg/kg, respectively. These are previously determined MTDs (12). For mouse experiments, eribulin was dissolved in 100% DMSO to produce a 10 mg/mL stock solution, which was stored at À80 C in single-use aliquots.…”

“…In the clinic and in animal systems, different microtubuletargeted drugs induce varying levels of neurotoxicity (11,12). For example, in mice treated for 2 weeks with the MTDs of the microtubule surface-binding drugs paclitaxel or ixabepilone, Wozniak and colleagues (12) observed significantly greater decreases in caudal and digital nerve conduction velocity and amplitude than were induced by the microtubule end-binding drug eribulin.…”

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

“…Colchicine, vinblastine, eribulin, and taccalonolide A have excellent persistence after washout, whereas paclitaxel and vinblastine do not Towle et al, 2011). One might expect that enhanced cellular persistence might be associated with more neurotoxicity, but this has not proven to be the case with eribulin (Wozniak et al, 2011). Cellular persistence can be useful for comparing drug analogs for in vivo testing, but cellular persistence alone cannot predict optimal antitumor response.…”

Eribulin Mesylate: Our Experience in a Real-Life Clinical Setting

“…По механизму действия он отличается от других тубулин-связывающих агентов, взаимодействуя преимущественно с небольшим числом высокоафинных сайтов на растущих плюс-концах микротрубочек [1][2][3][4][5], что позволяет избежать нежела-тельного воздействия препарата на нормальные физиоло-гические функции микротрубочек в неопухолевых клетках [6][7]. В отличие от других тубулин-связывающих агентов митотическая блокада эрибулином необратима, поэтому периодическое воздействие препарата приводит к стой-кой утрате жизнеспособности опухолевых клеток [8].…”