The usefulness of rabbits as an animal model for the neuropathological assessment of neurotoxicity following the administration of vincristine.
Vincristine is an effective chemotherapeutic agent for a variety of human neoplasms, but has dose-limiting neurotoxicity. Since laboratory rodents have proven to be refractive in such neurotoxicological studies, we conducted a neuropathological and behavioral assessment in rabbits treated with vincristine at doses known to be both chemotherapeutically effective and neurotoxic in humans. Rabbits (Kbl: NZW) were given vincristine intravenously at doses of 0 (saline), 200, 250 or 300 microg/kg once a week for 6 weeks, 500 microg/kg once a week for 3 weeks, or a single 500 microg/kg administration. Detailed periodic neurologic examination revealed ataxia in a few animals. Pathologically, axonal injury progressing to fiber degeneration was observed in sensory tracts such as the posterior spinocerebellar tract and posterior funiculus, and in peripheral nerves after treatment with vincristine. These alterations were observed even after a single dose of 500 microg/kg. In the group given weekly doses of 500 microg/kg, neuronal chromatolysis was also found in the spinal cord. These results suggest the rabbit is responsive to vincristine neurotoxicity producing a predominantly sensory neuropathy and confirming earlier studies.
Ogawa
T
T
Safety Research Department, Teikoku Hormone Mfg. Co., Ltd., Kanagawa, Japan. ogawa-t@kw.teikoku-hormone.co.jp
Mimura
Y
Y
Kato
H
H
Ootsubo
S
S
Murakoshi
M
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000473:pathology; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D009412:Nerve Fibers / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology* / Q000523:psychology; D011817:Rabbits; D012584:Sciatic Nerve / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology; D013997:Time Factors; D014750:Vincristine / Q000633:toxicity*
D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine