Carcinogen-induced unscheduled DNA synthesis in xenotransplanted human tracheobronchial epithelium: comparison with rat tracheal epithelium.
Extrapolation from rodent genotoxicity data to humans is complicated by variables such as interspecies differences in carcinogen metabolism and DNA repair. A xenograft system containing human bronchial epithelial cells was used to assess the induction of unscheduled DNA synthesis (UDS) by carcinogens and to compare the response with that of rat tracheal epithelium. Cells from human bronchus were grown in explant culture, inoculated into de-epithelialized rat tracheas and implanted subcutaneously into nude mice. Within six weeks, a differentiated mucociliary epithelium lined the xenografted tracheas. Fresh rat tracheas and human xenografts were cut into rings and incubated in media containing [3H]thymidine and either the direct-acting carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 3-1000 microM), or a carcinogen requiring metabolic activation, 4-nitroquinoline-1-oxide (4-NQO, 3-100 microM). Tissues were then fixed, sectioned, processed for autoradiography and the number of nuclear grains (NG) determined for 100 epithelial cells lining the trachea in each section. A time- and concentration-dependent increase in NG was observed in both human xenografts and rat tracheas after treatment with MNNG or 4-NQO, indicating induction of UDS by these agents. The UDS response to MNNG in the human xenografts was similar to that observed in the rat tracheas, whereas the response to 4-NQO was greater in rat tracheas. These studies indicate that the human xenograft system should have applications for the study of carcinogen-induced damage in normal bronchial epithelial cells.
Hesterberg, TW; Boreiko, CJ; Maness, SC; Iglehart, JD; Mangum, JB; Everitt, JI
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