title: Species and sex differences in susceptibility to olfactory lesions among the mouse, rat and monkey following an intravenous injection of vincristine sulphate.
abstract: Species and sex differences in susceptibility to vincristine sulphate (VCR)-induced olfactory epithelial lesions were investigated among the BALB/c mice, Crj: CD(SD) IGS rats and common marmoset monkeys following a single intravenous administration on day 1. As dosage levels, the 0.17-fold LD10, 0.6-fold LD10 and LD10 were used for mice and rats, and a maximum tolerated dose (MTD) was chosen only for monkeys. The order of strength of VCR action on peripheral neuropathic signs, body weight gain, and hematological parameters was mice > rats > monkeys, without clear sex differences. Histopathologically, on day 2, single cell death in the olfactory epithelium and vomeronasal organ was observed only in male mice at LD10, and in female mice at 0.6-fold LD10 or more. On day 5, the olfactory epithelium in these mice showed regenerative proliferation suggesting a sign of recovery. On day 10, axonopathy and demyelination in the sciatic and trigeminal nerves were noted in mice of both sexes at 0.6-fold LD10 or more. In rats and monkeys of either sex, however, no morphological changes were observed at any dose level. In conclusion, mice, particularly females, were shown to be more susceptible to VCR-induced apoptosis in the olfactory epithelium than rats and monkeys.
authors.affiliation: Drug Safety Research Laboratory, Daiichi Pharmaceutical Company Ltd., Tokyo, Japan. kaikitrx@daiichipharm.co.jp
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Kai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sahto
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Takami
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yukari
authors.initials: Y
authors.lastname: Shikanai
authors.forename: Tetsuyo
authors.initials: T
authors.lastname: Kajimura
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Furuhama
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002144:Callithrix; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D007633:Keratins / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009831:Olfactory Mucosa / Q000187:drug effects*; D051381:Rats; D020426:Sciatic Neuropathy / Q000139:chemically induced / Q000473:pathology; D012737:Sex Factors; D013045:Species Specificity; D020433:Trigeminal Nerve Diseases / Q000139:chemically induced / Q000473:pathology; D014750:Vincristine / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D007633:Keratins