The role of selenium in the prevention of cancer has been recently established by laboratory experiments, clinical trials, and epidemiological data. Most of the effects are related to the function of selenium in antioxidant enzyme systems. Animal data, epidemiological data, and intervention trials have shown a clear role for selenium derivatives in both prevention of specific cancers and antitumorigenic effects in postinitiation phases of cancer. Methods: Selenazolidine prodrugs (SCA) of selenocysteine were synthesized by the reaction of selenocysteine with the appropriate carbonyl derivative. Male CF1 mice were treated daily for 7 days with equi-selenium (1.25 mg Se/kg) doses of each agent, by either the intraperitoneal (ip) or intragastric (ig). route and the effects compared with those of selenocystine. Hepatic parameters were determined 24 hours after the last dose.The efficacy of SCA in reducing NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung adenomas in female A/J mice, a model for tobacco-related lung tumorigenesis, has been investigated with selenazolidines in the diet for 1 month prior to carcinogen administration and during the subsequent 4 months of tumor development. Results: In general, few significant (p <0.05) changes were seen with ig as compared to ip administration. 2-butylSCA, 2-cyclohexylSCA, 2-phenylSCA and 2-oxoSCA were chemopreventive, significantly reducing mean lung tumor numbers from the 10.9 of unsupplemented controls to 4.7, 5.3, 2.8 and 4.7, respectively. When selenazolidine supplementation began three days after carcinogen administration (i.e., post-initiation), 2-butylSCA, 2-cyclohexylSCA, and 2-oxoSCA were chemopreventive. In both regimens, selenocystine was also chemopreventive. Both 2-butylSCA and 2-phenylSCA retained their chemopreventive activity (44% and 40% tumor number reduction, respectively), when the supplementation was shortened and restricted to a pre-initiation period (days ?9 to?2). Conclusions: Although this study has not identified the mechanism, it firmly establishes that 2-substituted selenazolidine- 4(R)-carboxylic acids possess chemopreventive activity against NNK-induced lung tumors in a murine model. Dependent on the nature of the 2-substituent, the chemopreventive activity can arise from changes elicited in the post-initiation period, similar to selenocystine, or in the pre-initiation period.

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