[Tumor promotion and arachidonic acid cascades]

Chemical carcinogenesis can be subdivided at least into two stages, i.e., initiation and promotion, in the mouse skin carcinogenesis model. There is considerable evidence supporting the relevance of the above concept to chemical carcinogenesis of other organs. Initiation represents the stage in which a carcinogen interacts with DNA and causes irreversible damage on the genome. Subsequent repeated exposure to a tumor promoter leads to a phenotypic expression of the initiated cells to tumor cells. In our living environment, a larger number of carcinogens may exist and exposure to a minute amount of carcinogen even once may be sufficient to generate initiated cells; therefore, prevention of carcinogenesis at the stage of initiation is not an easy task. In contrast to the initiation stage, the promotion stage is essentially reversible, and a relatively long period is required to accomplish this process. Therefore, prevention of chemical carcinogenesis in the promotion stage seems more practical than preventing carcinogenesis in the initiation stage. There is much evidence suggesting that arachidonic acid cascades play important roles both in the initiation stages. There is much evidence suggesting that arachidonic acid cascades play important roles both in the initiation and promotion stages. In the two-stage skin carcinogenesis, inhibitors of arachidonic acid cascades, especially lipoxygenase inhibitors, effectively prevent tumor formation by inhibiting the stage of tumor promotion caused by different types of tumor promoters. Although at present, the role(s) of lipoxygenase pathways in the mechanism of tumor promotion is not fully understood, the potential use of lipoxygenase inhibitors for the prevention of chemical carcinogenesis is anticipated.