title: Neurotoxicity to DRG neurons varies between rodent strains treated with cisplatin and bortezomib.
abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect that can lead to long-term morbidity. Approximately one-third of patients receiving chemotherapy with taxanes, vinca alkaloids, platinum compounds or proteasome inhibitors develop this toxic side effect. It is not possible to predict who will get CIPN, however, genetic susceptibility may play a role. We explored this hypothesis using an established in vitro dorsal root ganglia neurite outgrowth (DRG-NOG) assay to assess possible genetic influences for cisplatin- and bortezomib-induced neurotoxicity. Almost all previous in vitro studies have used rats or mice. We compared DRG-NOG between four genetically defined, inbred mouse strains (C57BL/6J, DBA/2J, BALB/cJ, and C3H/HeJ) and one rat strain (Sprague Dawley). Our studies found differences in cisplatin and bortezomib-induced neurotoxicity between mouse and rat strains and between the different mouse strains. C57BL/6J and Balb/cJ DRG-NOG was more sensitive to cisplatin than DBA/2J and C3H/HeJ DRG-NOG, and all mouse strains were more sensitive to cisplatin than rat. Bortezomib induced a biphasic dose response in DBA/2J and C3H/H3J mice. C57BL/6J DRG-NOG was most sensitive and Balb/cJ DRG-NOG was least sensitive to bortezomib. Our animal data supports the hypothesis that genetic background may play a role in CIPN and care must be taken when rodent models are used to better understand the contribution of genetics in patient susceptibility to CIPN.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jewel L
authors.initials: JL
authors.lastname: Podratz
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Pleticha
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Staff
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: windebank.anthony@mayo.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Windebank
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008815:Mice, Inbred Strains; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D000069286:Bortezomib; D002945:Cisplatin
keywords: Bortezomib; Cisplatin; Genetic variations; Mouse strain; Neurite outgrowth; Neurotoxicity