Chemoprevention of oral carcinogenesis by DL-alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor: dose-dependent reduction in 4-nitroquinoline 1-oxide-induced tongue neoplasms in rats.

The modifying effect of three doses of DL-alpha-difluoromethylornithine (DFMO) given p.o. during the post-initiation phase of tongue carcinogenesis initiated by 4-nitroquinoline 1-oxide (4-NQO) was studied in male ACI/N rats. Animals were given 4-NQO at 20 ppm for 8 weeks in the drinking water to induce tongue neoplasms. One week after the stop of 4-NQO treatment, rats were transferred to the drinking water containing DFMO at concentrations of 100, 1000, and 2000 ppm for 25 weeks. The other groups consisted of rats given 2000 ppm DFMO alone or untreated rats. Thirty-four weeks after the start of the experiment, all animals were necropsied, and the incidences of neoplasms and preneoplastic lesions in the tongue, polyamine levels in the bloods and tongue tissues, and cell proliferation estimated by the number and area of silver-stained nucleolar organizer regions in the tongue epithelium were compared among the groups. Feeding of DFMO at all doses significantly inhibited the incidence of tongue neoplasms compared to the group given 4-NQO alone. DFMO at levels of 1000 and 2000 ppm significantly reduced the incidence of preneoplastic lesions of the tongue. Results analyzed by the linear regression method suggested a dose-dependent inhibition in the incidences of neoplastic and preneoplastic lesions of the tongue with increasing levels of DFMO. Increased levels in polyamines in the blood and tongue tissue were significantly suppressed by the treatment of DFMO. Also, silver-stained nucleolar organizer region indices were significantly reduced by the DFMO exposure. These results indicate that increasing levels of DFMO in the drinking water inhibited 4-NQO-induced tongue carcinogenesis in a dose-dependent manner and such inhibition was related to reduction in the polyamine levels of blood and tissue and decrease in the cell proliferation.