APPROACHES TO CANCER PREVENTION BASED ON AN UNDERSTANDING OF N-NITROSAMINE CARCINOGENESIS

Understanding carcinogenesis is critical for development of rational a pproaches to cancer prevention, This paper uses N-nitrosamine carcinog enesis as an example. N-Nitrosamines are a large group of potent carci nogens. Approximately 300 different N-nitrosamines are carcinogenic. A t least 30 animal species are responsive to their effects. There is li ttle doubt that humans exposed to sufficient amounts of N-nitrosamines would also be susceptible to their carcinogenic effects. Human exposu re to preformed N-nitrosamines occurs through the diet, in certain occ upational settings, and through the use of tobacco products, cosmetics , pharmaceutical products, and agricultural chemicals, Diminishing hum an exposure to these carcinogens is one approach to prevention of canc er, and this has been accomplished in many instances, although exposur e to N-nitrosamines in tobacco products is still unacceptably high. Hu man exposure to N-nitrosamines also occurs by nitrosation of amines in the body, via their acid or bacterial catalyzed reaction with nitrite , or by reaction with products of nitric oxide generated during inflam mation or infection. A second approach toward prevention of N-nitrosam ine carcinogenesis is inhibition of this endogenous N-nitrosamine form ation, Substantial reductions have been achieved with ascorbic acid an d other nitrite scavengers, N-Nitrosamines undergo a simple cytochrome P450-mediated metabolic activation step, which is critical for their carcinogenicity. The third approach involves the use of chemopreventiv e agents that block this step, or other steps in the carcinogenic proc ess. A large number of potent chemopreventive agents against nitrosami ne carcinogenesis have been identified. Chemoprevention of lung cancer induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-( 3-pyridyl)-1-butanone (NNK) is discussed as an example of this approac h.