Colorectal cancer chemoprevention: biochemical targets and clinical development of promising agents

Colorectal cancer (CRC) remains a cause: of significant mortality in developed countries despite extensive knowledge of its epidemiology and molecular basis. Since multiple molecular steps that collectively bring about this disease are known, its chemoprevention is a realistic proposition. Biochemical targets of CRC chemopreventive agents include carcinogen metabolising enzymes, arachidonic acid metabolism, the transcription factor nuclear factor-kappa beta (NF-kappaB), enzymes responsible for polyamine metabolism, and events associated with proliferation and apoptosis of preneoplastic cells. Aspirin, celecoxib, calcium and alpha -difluoromethylornithine are examples of drugs that have undergone clinical testing. Critical evaluation of these trials allows optimisation of methodologies for clinical advancement of novel chemopreventive: agents. Cancer patients can be a suitable cohort of subjects for pilot studies of certain new agents. Such studies and larger trials in high-risk healthy individuals require the stringent use of carefully validated 'preneoplastic' biomarkers which are intrinsically related to defined stages of colorectal carcinogenesis and/or to mechanisms of action of the agent under investigation. (C) 2001 Elsevier Science Ltd. All rights reserved.