Metabolic targets of cancer chemoprevention: interruption of tumor development by inhibitors of arachidonic acid metabolism.

Abstract

Tumor promotion is understood as a process that favors the clonal outgrowth of single mutated (initiated) cells to premalignant lesions through co-mitogenic and anti-apoptotic effects. This process can be evoked by repeated induction of a regenerative tissue response as achieved either by irritation and wounding or by agents (tumor promoters) that interact with the corresponding pathways of cellular signaling. Metabolic processes regulated by such pathways and essential for tumor development are potential targets of cancer chemoprevention. Examples are provided by the expression of ornithine decarboxylase and the activation of eicosanoid formation from arachidonic acid. Arachidonic acid metabolism is a particularly attractive and important target of chemopreventive measures. Its induction is a characteristic response to tissue damage and irritation and an apparently critical event in epithelial tumor promotion. Inhibitors of eicosanoid formation, such as nonsteroidal anti-inflammatory drugs, rank among the most powerful chemopreventive agents in animal models and have been shown to halve the incidence of colorectal cancer in man. Recently, the role of cyclooxygenase-2 (COX-2)-catalyzed prostaglandin synthesis has been the subject of much attention. COX-2 is a typical 'emergency enzyme', since in most tissues it is transiently induced only in the course of repair and defense reactions. In epithelial neoplasia, i.e. in skin and colorectal tumors, the enzyme is constitutively overexpressed along different molecular pathways, and it seems to be critically involved in tumor promotion. Consequently, specific COX-2 inhibitors have been shown to exhibit considerable cancer chemopreventive potential. The putative role of other pathways of arachidonic acid metabolism in tumor promotion and malignant progression is presently under investigation.