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 trigger ed by environmental genotoxic and non-genotoxic carcinogens, tumour progres sion becomes more and more autonomous at later stages. In this contest a dy sregulation 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 b ecause of their ability to inhibit prostaglandin biosynthesis, in particula r, 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 se ems to be a consistent feature of neoplastic development in a wide variety of tissues. COX-2 overexpression is thought to occur along signalling pathw ays 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). Prost aglandins formed along a dysregulated COX pathway have been shown to mediat e tumour promotion in animal experiments and may play a role, in addition, in other processes involved in tumour growth such as angiogenesis, metastas is and immunosuppression. Moreover, genotoxic byproducts such as organic fr ee radicals, ri active oxygen species and malondialdehyde produced in the c ourse of prostanoid biosynthesis may contribute to genetic instability (mut ator phenotype) of neoplastic cells thereby promoting malignant progression . Such mixtures of physiologically highly active mediators and genotoxic by products are, in addition, formed along the various lipoxy-genase-catalysed pathways of arachidonic acid metabolism some of which also become dysregul ated during tumour development and, therefore, provide novel targets of fut ure chemopreventive approaches, (C).: 2000 Elsevier Science Ltd. All rights reserved.