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Olfactory Epithelium as a Novel Toxic Target Following an Intravenous Administration of Vincristine to Mice
Kiyonori Kai
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan, kaikitrx{at}daiichipharm.co.jp
Hiroshi Satoh
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
Yoshinori Kashimoto
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
Tetsuyo Kajimura
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
Kazuhisa Furuhama
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
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 deoxyribonucleotidy l 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 histopathologica l evaluation of the nasal mucosa during an early preclinical stage for novel antitumor drugs, since olfactory lesions due to the certain compound s like VCR may not be detected by any other procedure.
Key Words: Apoptosis • nasal toxicity • olfactory sensory cells • vinca alkaloid.
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Toxicologic Pathology, Vol. 30, No. 3,
306-311 (2002)
DOI: 10.1080/01926230252929873
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