title: Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity.
abstract: Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332-9. ©2016 AACR.
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.affiliation: Medpace, Cincinnati, Ohio.
authors.forename: James J
authors.initials: JJ
authors.lastname: Vornov
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomoto
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: DesJardins
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: George
authors.initials: G
authors.lastname: Lai
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Larisa
authors.initials: L
authors.lastname: Reyderman
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wong
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Neurology, Medicine Psychiatry, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland. bslusher@jhmi.edu.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D034261:Epothilones / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000493:pharmacokinetics / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007659:Ketones / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014018:Tissue Distribution; D050257:Tubulin Modulators / Q000493:pharmacokinetics / Q000494:pharmacology; D000095662:Polyether Polyketides
chemical_list: D034261:Epothilones; D005663:Furans; D007659:Ketones; D017239:Paclitaxel; D050257:Tubulin Modulators; C430592:ixabepilone; C490954:eribulin; D000095662:Polyether Polyketides