Olfactory Epithelial Lesions Induced by Various Cancer Chemotherapeutic Agents in Mice

Abstract

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.

Keywords

Antitumor drugs olfactory toxicity sensory cells apoptosis mice.

References

Barber, P.C. , and Raisman, G. (1978). Cell division in the vomeronasal organ of the adult mouse. Brain Res 141, 57—66.

Bayssas, M. , Gouveia, J. , de Vassal, F. , Misset, J.L. , Schwarzenberg, L. , Ribaud, P. , Musset, M. , Jasmin, C. , Hayat, M. , and Mathe, G. (1980). Vindesine: a new vinca alkaloid. Recent Results Cancer Res 74, 91—7.

Brenneman, K.A. , Meleason, D.F. , Sar, M. , Marshall, M.W. , James, R.A. , Gross, E.A. , Martin, J.T. , and Dorman, D.C. (2002). Olfactory mucosal necrosis in male CD rats following acute inhalation exposure to hydrogen sulfide: reversibility and the possible role of regional metabolism. Toxicol Pathol 30, 200—8.

Cleton, F.J. (1995). Chemotherapy: general aspects. In Oxford Textbook of Oncology ( Peckham, M. , Pinedo, H. , Veronesi, V. , eds.), pp. 445—53. Oxford University Press, Oxford.

Gottschalk, P.G. , Dyck, P.J. , and Kiely, J.M. (1968). Vinca alkaloid neuropathy: nerve biopsy studies in rats and in man. Neurology 9, 875—82.

Hirano, G. , and Miyazaki, K. (1998). Anosmia caused by fluorouracil derivatives. Nichi Kan Yakuji 40, 877—9.

Huard, J.M. , and Schwob, J.E. (1995). Cell cycle of globose basal cells in rat olfactory epithelium. Dev Dyn 203, 17—26.

Japanese Association for Laboratory Animal Science (1987). Guidelines for animal experimentation. Exp Anim 36, 285—8.

Kai, K. , Satoh, H. , Kashimoto, Y. , Kajimura, T. , and Furuhama, K. (2002). Olfactory epithelium as a novel toxic target following an intravenous administration of vincristine to mice. Toxicol Pathol 30, 306—11.

10.

Kanter, P.M. , Klaich, G.M. , Bullard, G.A. , King, J.M. , Bally, M.B. , and Mayer, L.D. (1994). Liposome encapsulated vincristine: preclinical toxicologic and pharmacologic comparison with free vincristine and empty liposome in mice, rats, and dogs. Anticancer Drug 5, 579—90.

11.

Kastner, A. , Moyse, E. , Bauer, S. , Jourdan, F. , and Brun, G. (2000). Unusual regulation of cyclin D1 and cyclin-dependent kinases cdk2 and cdk4 during in vivo mitotic stimulation of olfactory neuron progenitors in adult mouse. J Neurochem 74, 2343—9.

12.

Kohler, D.R. , and Goldspiel, B.R. (1994). Paclitaxel (taxol). Pharmacotherapy 14, 3—34.

13.

Koja, S. , Itokazu, T. , Kamiya, S. , Maeshiro, N. , Yamauchi, M. , Esu, H. , Simoji, Y. , Kanazawa, T. , and Noda, Y. (1994). Tissue concentration of tegafur suppository in patients with head and neck cancer concentration of 5-FU in cancer tissue . Gan To Kagaku Ryoho 21, 981—5.

14.

Kuhn, J.G. (2001). Fluorouracil and the new oral fluorinated pyrimidines . Ann Pharmacother 35, 217—27.

15.

Mery, S. , Gross, E.A. , Joyner, D.R. , Godo, M. , and Morgan, K.T. (1994). Nasal diagram: a tool for recording the distribution of nasal lesion in rats and mice. Toxicol Pathol 22, 353—72.

16.

Morgan, K.T. (1994). Nasal dosimetry, lesion distribution, and the toxicologic pathologist: a brief review. Inhal Toxicol 6, 41—57.

17.

Morgan, K.T. , and Harkema, J.R. (1996). Nonneoplastic lesions of the olfactory mucosa , In Respiratory System, Monographs on Pathology of Laboratory Animals, 2nd ed. ( T. C. Jones , D. L. Dungworth , and U. Mohr , eds.). pp. 28—43. Springer-Verlag

Berlin

Heidelberg, New York.

18.

Nakamura, H. , Nonomura, N. , Fujiwara, M. , and Nakano, Y. (1995). Olfactory disturbances caused by the anti-cancer drug tegafur. Eur Arch Otorhinolaryngol 252, 48—52.

19.

O'Marcaigh, A.S. , and Betcher, D.L. (1995). The vinca alkaloids. J Pediatr Oncol Nurs 12, 140—2.

20.

Onetto, N. , Canetta, R. , Winograd, B. , Catane, R. , Dougan, M. , Grechko, J. , Burroughs, J. , and Rozencweig, M. (1993). Overview of taxol safety. J Natl Cancer Inst Monogr 15, 131—9.

21.

Quasthoff, S. , and Hartung, H.P. (2002). Chemotherapy-induced peripheral neuropathy. J Neurol 249, 9—17.

22.

Reed, E. (1999). Cisplatin. Cancer Chemother Biol Response Modif 18, 144—51.

23.

Robinson, D.A. , Foster, J.R. , Nash, J.A. , and Reed, C.J. (2003). Three-dimensional mapping of the lesions induced by beta-beta'iminodiproprionitrile, methyl iodide and methyl methacrylate in the rat nasal cavity. Toxicol Pathol 31, 340—7.

24.

Schwartz, L.M. , Chikaraishi, D.M. , and Kauer, J.S. (1991). Characterization of potential precursor populations in the mouse olfactory epithelium using immunocytochemistry and autoradiography . J Neurosci 11, 3556—64.

25.

Suzuki, Y. , and Takeda, M. (1991). Basal cells in the mouse olfactory epithelium after axotomy: immunohistochemical and electoton-microscopic studies. Cell Tissue Res 266, 239—45.

26.

Suzuki, Y. , Takeda, M. , and Farbman, A.I. (1996). Supporting cells as phagocyte in the olfactory epithelium after bulbectomy. J Comp Neurol 376, 509—17.

27.

Suzuki, Y. , Takeda, M. , Obara, N. , and Suzuki, N. (1998). Bulbectomy of neonatal mice induces migration of basal cells from the olfactory epithelium. Brain Res Dev Brain Res 108, 295—298.

28.

Suzuki, Y. , Takeda, M. , Obara, N. , Suzuki, N. , and Takeichi, N. (2000). Olfactory epithelium consisting of supporting cells and horizontal basal cells in the posterior nasal cavity of mice. Cell Tissue Res 299, 313—25.

29.

Todd, G.C. , Gibson, W.R. , and Morton, D.M. (1976). Toxicology of vindesine (desacetyl vinblastine amide) in mice, rats, and dogs. J Toxicol Environ Health 1, 843—50.

30.

Todd, G.C. , Griffing, W.J. , Gibson, W.R. , and Morton, D.M. (1979). Animal models forthe comparative assessment of neurotoxicity following repeated administration of vinca alkaloids. Cancer Treat Rep 63, 35—41.

31.

Verweij, J. , Sparreboom, A. , and Nooter, K. (1999). Mitomycins. Cancer Chemother Biol Response Modif 18, 46—58.

32.

Wang, L.G. , Liu, X.M. , Kreis, W. , and Budman, D.R. (1999). The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol 44, 355—61.

33.

Wilson, K.C. , and Raisman, G. (1980). Age-related changes in the neurosensory epithelium of the mouse vomeronasal organ: extended period of postnatal growth in size and evidence for rapid cell turnover in the adult. Brain Res 185, 103—13.

34.

Yaku, Y. , and Saruta, T. (1986). Ultrastructural studies of the olfactory epithelium following bulbectomy evidence of neuronal regeneration. Nippon Jibiinkoka Gakkai Kaiho 89, 1777—86.

35.

Zhou, X.J. , and Rahmani, R. (1992). Preclinical and clinical pharmacology of vinca alkaloids. Drugs 44, 1—16.