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1,4-Phenylenebis(methylene)selenocyanate Exerts Exceptional Chemopreventive Activity in Rat Tongue Carcinogenesis¹

Departments of Pathology [T. T., K. K., H. Mo.] and Oral and Maxillo-Facial Surgery [H. Ma.], Gifu University School of Medicine, 40 Tsukasa-machi, Gifu City 500, Japan; and Division of Cancer Etiology and Prevention [K. E-B.], American Health Foundation, Valhalla, New York 10595

Among the organoselenium compounds, 1,4-phenylenebis(methylene) selenocyanate (p-XSC) is reported to exert the most effective chemopreventive effect on chemically induced carcinogenesis in the mammary glands, colon, and lung of laboratory animals. This study was designed to test the inhibitory effects of dietary p-XSC (5 and 15 ppm as selenium) during the initiation phase (1 week before, during, and up to 1 week after the carcinogen exposure) and the postinitiation phase (1 week after carcinogen administration until termination) on the formation of neoplasms of the tongue induced in male F344 rats by 4-nitroquinoline-1-oxide (4-NQO). The doses of p-XSC were 20% (5 ppm selenium) and 60% (15 ppm selenium) of maximum tolerated dose levels. At 6 weeks of age, all rats except those given p-XSC alone and those in untreated groups were treated with 4-NQO (20 ppm in the drinking water for 8 weeks). Dietary p-XSC, administered at selenium levels of 5 and 15 ppm during either the initiation or postinitation phases, significantly reduced the incidence of carcinoma of the tongue. p-XSC was especially effective when it was administered at 15 ppm selenium during the postinitiation phase, in which case it completely inhibited the development of tongue carcinoma (from 47% in the dietary control to 0%). Glutathione S-transferase activities in the liver and tongue of rats treated with 4-NQO and p-XSC were significantly elevated compared to those in rats treated with 4-NQO alone. Similarly, quinone reductase activity was significantly elevated in the liver but decreased in the tongue (posterior portion). Such modulation by p-XSC in the phase II enzyme activities of the liver and tongue might be related to inhibition of the initiation. In addition, the expression of cell proliferation biomarkers, such as polyamine level, ornithine decarboxylase activity, 5-bromodexyuridin-labeling index, and argyrophilic nucleolar organizer's protein number, in the epithelium of the tongue was significantly reduced in rats that were fed the p-XSC diets compared to those who were fed the basal diet. Such alteration in cell proliferation through modulation of ornithine decarboxylase activity and polyamine biosynthesis in the tongue epithelium might be related to inhibition occurring in the postinitiation phase of carcinogenesis. The dose levels of p-XSC used induced no toxicity or alteration in body weight gain. Although the precise mechanisms of p-XSC-induced inhibition of tongue carcinogenesis remains to be elucidated, it is evident that p-XSC has powerful chemopreventive efficacy against tongue carcinogenesis.

¹ This work was supported in part by Grants-in-Aid from the Ministry of Education, Science and Sports (Japan), by the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare (Japan), and by National Cancer Institute Grant PO1-70972.

² To whom requests for reprints should be addressed.

Received 5/23/97. Accepted 7/17/97.

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