Cancer chemoprevention through interruption of multistage carcinogenesis. The lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer.

Whilst in the early stages, neoplastic development is predominantly triggered by environmental genotoxic and non-genotoxic carcinogens, tumour progression becomes more and more autonomous at later stages. In this context a dysregulation of arachidonic acid metabolism seems to play a disastrous role. Conversely, non-steroidal anti-inflammatory drugs (NSAIDs) rank among the most potent and most promising agents for cancer chemoprevention probably because of their ability to inhibit prostaglandin biosynthesis, in particular, at the level of the 'pro-inflammatory' enzyme cyclooxygenase-2 (COX-2). A pathological overexpression of COX-2 resulting in excessive prostaglandin production has been found already in early stages of carcinogenesis and seems to be a consistent feature of neoplastic development in a wide variety of tissues. COX-2 overexpression is thought to occur along signalling pathways of inflammation and tissue repair which become activated in the course of tumour promotion and, due to autocrine and auto-stimulatory mechanisms, finally lead to some autonomy of tumour development (self-promotion). Prostaglandins formed along a dysregulated COX pathway have been shown to mediate tumour promotion in animal experiments and may play a role, in addition, in other processes involved in tumour growth such as angiogenesis, metastasis and immunosuppression. Moreover, genotoxic byproducts such as organic free radicals, reactive oxygen species and malondialdehyde produced in the course of prostanoid biosynthesis may contribute to genetic instability (mutator phenotype) of neoplastic cells thereby promoting malignant progression. Such mixtures of physiologically highly active mediators and genotoxic byproducts are, in addition, formed along the various lipoxygenase-catalysed pathways of arachidonic acid metabolism some of which also become dysregulated during tumour development and, therefore, provide novel targets of future chemopreventive approaches.