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Toxicologic Pathology
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Olfactory Epithelial Lesions Induced by Various Cancer Chemotherapeutic Agents in Mice

Kiyonori Kai

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan, kaikitrx{at}daiichipharm.co.jp

Hiroshi Satoh

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan

Tetsuyo Kajimura

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan

Michiyuki Kato

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan

Kazuyuki Uchida

Department of Veterinary Pathology, Faculty of Agriculture, Miyazaki University, Miyazaki 889-2155, Japan

Ryoji Yamaguchi

Department of Veterinary Pathology, Faculty of Agriculture, Miyazaki University, Miyazaki 889-2155, Japan

Susumu Tateyama

Department of Veterinary Pathology, Faculty of Agriculture, Miyazaki University, Miyazaki 889-2155, Japan

Kazuhisa Furuhama

Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan

In order to examine and compare the potential toxicity in the olfactory epithelium, the antitumor drug vincristine sulfate (VCR), vinblastine sulfate (VBL), vindesine sulfate (VDS), paclitaxel (PTX), mitomycin C (MMC), 5-fluorouracil, (5-FU) or cisplatin (CDDP) was intravenously injected once (designated as day 1) at an estimated 10% lethal dose (LD10) to male BALB/c mice. The animals were necropsied on days 2, 5 and 15, and nasal tissues were examined by light-microscopy, counting of epithelial cells positive for terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL), immunohistochemical staining with keratin antibody, and electron microscopy. Further, to delineate the drug disposition in the target organ, whole-body radioluminography was performed 1 hour and 24 hours after treatment with the LD10 of PTX or 5-FU. Of the antitumor drugs employed, only the antimicrotubule agents, VCR, VBL, VDS, and PTX, induced single cell death in the olfactory epithelium, especially sensory cells on day 2, atrophy of the olfactory epithelium on day 5, and myelin fragmentation in the trigeminal nerve on day 15. PTX induced the strongest changes among the 4 antimicrotubule agents. The cell death was confirmed to be apoptosis by TUNEL assay and electron microscopy, whereas the change in horizontal basal cells of the olfactory epithelium was shown not to be apoptosis by keratin staining. In quantitative radioluminography, radioactivity of PTX in the nasal tissues both 1 hour and 24 hours after administration was about 4- or 5-fold higher than those of 5-FU. These results suggest that tubulin-targeting antitumour drugs could induce apoptosis in the olfactory epithelial cells of mice and that high drug distribution may effect the onset of the olfactory lesions.

Key Words: Antitumor drugs • olfactory toxicity • sensory cells • apoptosis • mice.

Toxicologic Pathology, Vol. 32, No. 6, 701-709 (2004)
DOI: 10.1080/01926230490524283
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 Toxicol PatholHome page
A. M. Jeffrey, M. J. Iatropoulos, and G. M. Williams
Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals
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[Abstract] [Full Text] [PDF]