title: Vincristine and bortezomib cause axon outgrowth and behavioral defects in larval zebrafish.
abstract: Peripheral neuropathy is a common side effect of a number of pharmaceutical compounds, including several chemotherapy drugs. Among these are vincristine sulfate, a mitotic inhibitor used to treat a variety of leukemias, lymphomas, and other cancers, and bortezomib, a 26S proteasome inhibitor used primarily to treat relapsed multiple myeloma and mantle cell lymphoma. To gain insight into the mechanisms by which these compounds act, we tested their effects in zebrafish. Vincristine or bortezomib given during late embryonic development caused significant defects at both behavioral and cellular levels. Intriguingly, the effects of the two drugs appear to be distinct. Vincristine causes uncoordinated swimming behavior, which is coupled with a reduction in the density of sensory innervation and overall size of motor axon arbors. Bortezomib, in contrast, increases the duration and amplitude of muscle contractions associated with escape swimming, which is coupled with a preferential reduction in fine processes and branches of sensory and motor axons. These results demonstrate that zebrafish is a convenient in vivo assay system for screening potential pharmaceutical compounds for neurotoxic side effects, and they provide an important step toward understanding how vincristine and bortezomib cause peripheral neuropathy.
authors.affiliation: Department of Biology, Williams College, Williamstown, MA, USA.
authors.forename: Tahsin M
authors.initials: TM
authors.lastname: Khan
authors.forename: Nathan
authors.initials: N
authors.lastname: Benaich
authors.forename: Clare F
authors.initials: CF
authors.lastname: Malone
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Bernardos
authors.forename: Amy R
authors.initials: AR
authors.lastname: Russell
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Downes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Barresi
authors.forename: Lara D
authors.initials: LD
authors.lastname: Hutson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects*; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D007150:Immunohistochemistry; D007814:Larva / Q000187:drug effects; D011719:Pyrazines / Q000009:adverse effects*; D014750:Vincristine / Q000009:adverse effects*; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib