Sustained accumulation of microtubule-binding chemotherapy drugs in the peripheral nervous system: Correlations with time course and neurotoxic severity

Krystyna M. Wozniak, James J. Vornov, Ying Wu, Kenichi Nomoto, Bruce A. Littlefield, Christopher DesJardins, Yanke Yu, George Lai, Larisa Reyderman, Nancy Wong, Barbara Slusher

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3332-3339
Number of pages8
JournalCancer Research
Volume76
Issue number11
DOIs
StatePublished - Jun 1 2016

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Peripheral Nervous System Agents
eribulin
Paclitaxel
Nerve Tissue
Microtubules
Peripheral Nerves
Drug Therapy
Spinal Ganglia
Sciatic Nerve
Pharmaceutical Preparations
Pharmacokinetics
Peripheral Nervous System
Peripheral Nervous System Diseases
Tissue Distribution
Antineoplastic Agents

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sustained accumulation of microtubule-binding chemotherapy drugs in the peripheral nervous system : Correlations with time course and neurotoxic severity. / Wozniak, Krystyna M.; Vornov, James J.; Wu, Ying; Nomoto, Kenichi; Littlefield, Bruce A.; DesJardins, Christopher; Yu, Yanke; Lai, George; Reyderman, Larisa; Wong, Nancy; Slusher, Barbara.

In: Cancer Research, Vol. 76, No. 11, 01.06.2016, p. 3332-3339.

Research output: Contribution to journalArticle

Wozniak, KM, Vornov, JJ, Wu, Y, Nomoto, K, Littlefield, BA, DesJardins, C, Yu, Y, Lai, G, Reyderman, L, Wong, N & Slusher, B 2016, 'Sustained accumulation of microtubule-binding chemotherapy drugs in the peripheral nervous system: Correlations with time course and neurotoxic severity', Cancer Research, vol. 76, no. 11, pp. 3332-3339. https://doi.org/10.1158/0008-5472.CAN-15-2525
Wozniak, Krystyna M. ; Vornov, James J. ; Wu, Ying ; Nomoto, Kenichi ; Littlefield, Bruce A. ; DesJardins, Christopher ; Yu, Yanke ; Lai, George ; Reyderman, Larisa ; Wong, Nancy ; Slusher, Barbara. / Sustained accumulation of microtubule-binding chemotherapy drugs in the peripheral nervous system : Correlations with time course and neurotoxic severity. In: Cancer Research. 2016 ; Vol. 76, No. 11. pp. 3332-3339.
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