title: 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 microtubule-targeting 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 × MTD, 0.5 × MTD, 0.75 × 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.
authors.affiliation: Johns Hopkins Brain Science Institute, Baltimore, Maryland 21205, USA. kwoznia3@jhmi.edu
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomoto
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Valentina
authors.initials: V
authors.lastname: Carozzi
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Hosokawa
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Towle
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000633:toxicity*; D005260:Female; D005663:Furans / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects; D007659:Ketones / Q000633:toxicity*; D008698:Mesylates / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009431:Neural Conduction / Q000187:drug effects; D017239:Paclitaxel / Q000633:toxicity*; D011115:Polyneuropathies / Q000139:chemically induced*; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects; D050257:Tubulin Modulators / Q000633:toxicity; D000095662:Polyether Polyketides
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D034261:Epothilones; D005663:Furans; D007659:Ketones; D008698:Mesylates; D017239:Paclitaxel; D050257:Tubulin Modulators; C430592:ixabepilone; C490954:eribulin; D000095662:Polyether Polyketides