Inhibitory effect of retinoid on esophageal carcinogenesis in rats induced by N-nitroso-N-methylbutylamine in relation to cellular retinoic acid-binding protein.

The inhibitory effect of a synthetic retinoid, ethyl alltrans-9-(4-methoxy-2, 3, 6-trimethyl-phenyl)-3, 7-dimethyl-2, 4, 6, 8-nonatetraenoate (Tigason), on esophageal carcinogenesis in F344 rats induced by N-nitroso-N-methylbutylamine (NMBA) was evaluated. The animals were given NMBA daily in their drinking water for 21 weeks at a concentration of 15 mg per liter ad libitum starting at 8 weeks of age. One week before the beginning of NMBA treatment, the rats were divided randomly into Tigason-fed and -unfed groups. Thirty-five rats were fed a diet supplemented with Tigason at a concentration of 30 mg per kg of diet, and 80 rats were given a basal diet alone. In NMBA-treated rats, multiple papillomas were seen 11 weeks after NMBA treatment and squamous cell carcinoma developed 12 weeks after NMBA; the tumors increased in number thereafter, and the numbers of papillomas and carcinomas were the same at 17 and 21 weeks after NMBA. At 21 weeks after NMBA treatment, the number of papillomas was similar, regardless of the dietary Tigason supplement, however, the number of esophageal squamous cell carcinomas was significantly lower in the Tigason-fed rats than in -unfed animals (p < 0.025). In normal esophageal tissues, a small amount of cellular retinoic acid-binding protein (cRABP) was detected throughout the experimental period, while during carcinogenesis, the levels of cRABP increased continuously until 16 weeks after NMBA; the cRABP level was higher in papillomas than in squamous cell carcinomas. As Tigason specificially blocked the progression of papillomas to carcinomas, it may be a promising candidate chemopreventive agent in esophageal carcinogenesis.