TY - JOUR
T1 - Peripheral neuropathy induced by microtubule-targeted chemotherapies
T2 - Insights into acute injury and long-term recovery
AU - Wozniak, Krystyna M.
AU - Vornov, James J.
AU - Wu, Ying
AU - Liu, Ying
AU - Carozzi, Valentina A.
AU - Rodriguez-Menendez, Virginia
AU - Ballarini, Elisa
AU - Alberti, Paola
AU - Pozzi, Eleonora
AU - Semperboni, Sara
AU - Cook, Brett M.
AU - Littlefield, Bruce A.
AU - Nomoto, Kenichi
AU - Condon, Krista
AU - Eckley, Sean
AU - DesJardins, Christopher
AU - Wilson, Leslie
AU - Jordan, Mary A.
AU - Feinstein, Stuart C.
AU - Cavaletti, Guido
AU - Polydefkis, Michael
AU - Slusher, Barbara S.
N1 - Funding Information:
These studies were funded by a research support agreement from Eisai Inc., an NIH grant R01CA161056 (to B.S. Slusher), and utilized a NRI-MCDB Microscopy Facility at University of California (Santa Barbara, CA) supported by NIH S10OD010610.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice. Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors.
AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice. Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors.
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U2 - 10.1158/0008-5472.CAN-17-1467
DO - 10.1158/0008-5472.CAN-17-1467
M3 - Article
C2 - 29191802
AN - SCOPUS:85041557957
SN - 0008-5472
VL - 78
SP - 817
EP - 829
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -