Comparison of the Chemopreventive Efficacies of 1,4-phenylenebis(methylene)selenocyanate and Selenium-Enriched Yeast on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induced Lung Tumorigenesis in A/J Mouse

Abstract

Epidemiological studies, clinical intervention trials (including the trial with selenium-enriched yeast by Clark et al. JAMA 276, 1957, 1996) and assays in laboratory animals provide evidence for a protective role of selenium against the development of several cancers, including lung cancer. We have demonstrated that selenium in the form of 1,4 phenylenebis (methylene) selenocyanate (p-XSC) is a promising chemopreventive agent in the A/J mouse lung tumor model induced with the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); under identical conditions, selenomethionine (SM), a component of selenium-enriched yeast, had no effect. The lack of an effect of SM suggests that other forms of selenium, or selenium-enriched yeast as a whole, are essential for lung cancer prevention; moreover, various species may respond differently to a given form of selenium. Therefore, in this study, we compared the chemopreventive efficacies of p-XSC with selenium-enriched yeast. Groups of 5-wk-old mice were fed either control diet or experimental diet containing p-XSC (5 or 10 ppm as selenium, equivalent to 20% and 40% maximum tolerated dose [MTD], respectively) or selenium-enriched yeast (5 or 10 ppm). Beginning at Wk 7, each mouse received NNK (3 ?mol) in 0.1 ml cottonseed oil by intragastric intubation, once weekly for 8 wk. Twenty-six weeks after the first NNK administration, mice were killed and tumors in lung and forestomach were counted. p-XSC at 5 and 10 ppm doses significantly reduced lung tumor induction by NNK from 10.4 ±6.0 (multiplicity) to 2.7±1.5 (P<0.001) and 1.8&plusmn2.0 (P< 0.0001) respectively, whereas selenium-enriched yeasthadno effect. p-XSC at 10 ppm also significantly reduced the incidence level from 96% to 68% (P < 0.01). The amounts of selenium that reach the target organ (lung) after dietary administration of p-XSC (326 ± 69 ng Se/g lung tissue) were significantly higher than that from selenium-enriched yeast (34±8.5 ng Se/g lung tissue). However, the levels of selenium in plasma from selenium-enriched yeast (620 ± 54 ng Se/g plasma) were twofold higher than those fromp-XSC (355±85 ng Se/g plasma). In biochemical studies, p-XSC was shown to significantly inhibit formation ofO6-methylguanine (O6-MG) and 7-methylguanine (7-MG) in the lungs and livers of mice treated with NNK. The lack of effect of selenium-enriched yeast on these lesions agrees with the results of the bioassay. Collectively, the results of this study clearly indicate that as a chemopreventive agent, p-XSC is superior to selenium-enriched yeast under the conditions of the present protocol. The inhibition ofDNA methylation and the significantly higher retention of selenium from p-XSC as compared with selenium- enriched yeast in the target organ may in part account