This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Keenan, K. P. Articles by McDowell, E. M. Search for Related Content PubMed PubMed Citation Articles by Keenan, K. P. Articles by McDowell, E. M.

Multifactorial Hamster Respiratory Carcinogenesis with Interdependent Effects of Cannula-induced Mucosal Wounding, Saline, Ferric Oxide, Benzo[a]pyrene and N-Methyl-N-nitrosourea¹

Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201 [K. P. K., E. M. M.]; Laboratory of Experimental Pathology, National Cancer Institute, Bethesda, MD 20892 [U. S., S. F. S.]; and Computer and Statistical Services, Data Management Services, Inc., National Cancer Institute, Division of Cancer Etiology Frederick Cancer Research Facility, Frederick, Maryland 21701 [C. W. R.]

The carcinogenic response induced in the respiratory tract of Syrian golden hamsters by repeated intratracheal instillations of benzo[a]pyrene (BP) adsorbed to ferric oxide (Fe₂O₃) particles suspended in saline, is shown to result from the interactions of these factors and cannula-induced tracheal wounding. Previous acute studies of intratracheal cannulation (ITC) versus intralaryngeal cannulation (ILC) showed that tracheal cell proliferation increased significantly in ITC-induced mucosal wounds. Only mild increases in intrapulmonary cell proliferation were produced by Fe₂O₃-saline given by ILC or ITC (Keenan et al., Cancer Res., 49: 1521–1527, 1989). The present chronic studies included the following variables: a single instillation by ILC of N-methyl-N-nitrosourea (MNU) at 5 weeks of age; 15 weekly treatments (beginning at 7 weeks of age) by ILC or ITC alone, or with instillations of saline, or Fe₂O₃-saline, or BP-Fe₂O₃-saline; and appropriate controls.

Repeated ITC-induced tracheal wounds caused persistent tracheal epithelial hyperplasia, metaplasia and/or atrophy and submucosal fibroplasia during the observation period of 22 to 78 weeks of age (the time of terminal sacrifice). Tracheal cancers (in situ or invasive carcinomas) were seen only in those hamsters which had received repeated ITC and one or both carcinogens. The cancer latency was shortest and the incidence of tracheal (50%) and main-stem bronchial (21%) cancers highest in hamsters given MNU and repeated ITC with BP-Fe₂O₃-saline. Hamsters given carcinogens by ILC (which induced laryngeal but not tracheal wounds) developed proliferative lesions and cancers of the larynx but no tracheobronchial cancers. These data show the singular importance of repeated ITC-induced intratracheal wounding as an enhancing factor in this respiratory carcinogenesis model. The findings suggest that the mechanism of tumor enhancement involves not only changes in target epithelial cell proliferation, but also alterations in normal epithelial-mesenchymal interactions during tracheal regeneration from repeated chronic submucosal inflammation and mesenchymal repair.

In the present experimental model, a single dose of MNU at 5 weeks of age, repeated instilled doses of BP, and tracheal mucosal wounding were each found to be important determinants of the carcinogenic response. Additional effects were observed for instilled Fe₂O₃ particles, and possibly saline. Interplay of all these factors, as well as of genetic, nutritional, and infectious factors, are considered in relation to risk assessment and prevention.

¹ Supported by National Cancer Institute Contract N01-CP-26505 (E.M.M.); and a Pharmaceutical Manufacturers Association Faculty Development Award (K.P.K.).

² Present address: Department of Safety Assessment, Building WP 44-1, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.

³ To whom requests for reprints should be addressed at: Department of Pathology, University of Maryland School of Medicine, 10 South Pine Street, Baltimore, MD 21201.

Received 4/22/88. Revised 11/14/88. Accepted 12/13/88.

This article has been cited by other articles:

				T. G. Harris, S. L. Kulasingam, N. B. Kiviat, C. Mao, S. N. Agoff, Q. Feng, and L. A. Koutsky Cigarette Smoking, Oncogenic Human Papillomavirus, Ki-67 Antigen, and Cervical Intraepithelial Neoplasia Am. J. Epidemiol., May 1, 2004; 159(9): 834 - 842. [Abstract] [Full Text] [PDF]

				S. Garry, F. Nesslany, E. M. Aliouat, J.-M. Haguenoer, and D. Marzin Potent genotoxic activity of benzo[a]pyrene coated onto hematite measured by unscheduled DNA synthesis in vivo in the rat Mutagenesis, September 1, 2003; 18(5): 449 - 455. [Abstract] [Full Text] [PDF]

				Y. Tsurudome, T. Hirano, H. Yamato, I. Tanaka, M. Sagai, H. Hirano, N. Nagata, H. Itoh, and H. Kasai Changes in levels of 8-hydroxyguanine in DNA, its repair and OGG1 mRNA in rat lungs after intratracheal administration of diesel exhaust particles Carcinogenesis, August 1, 1999; 20(8): 1573 - 1576. [Abstract] [Full Text] [PDF]