Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity
Autor: | James J. Vornov, Ying Wu, Kenichi Nomoto, Larisa Reyderman, Nancy Wong, Christopher DesJardins, Yanke Yu, Bruce A. Littlefield, Krystyna M. Wozniak, W. George Lai, Barbara S. Slusher |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Eribulin Mesylate Cancer Research Time Factors Paclitaxel Blotting Western Apoptosis Pharmacology Microtubules Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Ganglia Spinal medicine Animals Tissue Distribution Furans Cell Proliferation Mice Inbred BALB C Dose-Response Relationship Drug business.industry Neurotoxicity Peripheral Nervous System Diseases Ketones medicine.disease Sciatic Nerve Tubulin Modulators Electrophysiology 030104 developmental biology medicine.anatomical_structure Peripheral neuropathy Oncology chemistry Epothilones Peripheral nervous system Female Sciatic nerve business 030217 neurology & neurosurgery Eribulin |
Zdroj: | Cancer Research. 76:3332-3339 |
ISSN: | 1538-7445 0008-5472 |
Popis: | 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. |
Databáze: | OpenAIRE |
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