Olfactory epithelium as a novel toxic target following an intravenous administration of vincristine to mice.
To delineate morphological characteristics of olfactory lesions induced by vincristine (VCR), a vinca alkaloid derivative with antitumor activity, male BALB/c mice were given a single intravenous injection of 1.95 mg/kg, an estimated 10% lethal dose (designated as day 1). The animals were serially sacrificed on days 2, 3, 5, 10, 15 and 60, and the nasal mucosa was examined histopathologically. Cell death was noted in the olfactory epithelia adjacent to the respiratory epithelia from days 2 to 5. Inflammatory responses were not detected throughout the observation periods. Cell death was identified as apoptotic by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay and electron microscopy. Mitotic figures and proliferating cell nuclear antigen (PCNA)-positive reactions were diffusely scattered in both the basal and sensory cells. On days 10 or after, no prominent histological abnormalities were noted in the olfactory epithelia, which suggests the aforementioned lesions were completely recovered. These results demonstrate that it is essential to perform histopathological evaluation of the nasal mucosa during an early preclinical stage for novel antitumor drugs, since olfactory lesions due to the certain compounds like VCR may not be detected by any other procedure.
Kai
Kiyonori
K
Drug Safety Reseach Laboratory, Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan. kaikitrx@daiichipharm.co.jp
Satoh
Hiroshi
H
Kashimoto
Yoshinori
Y
Kajimura
Tetsuyo
T
Furuhama
Kazuhisa
K
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000648:ultrastructure*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects*
D000972:Antineoplastic Agents, Phytogenic; D018809:Proliferating Cell Nuclear Antigen; D014750:Vincristine