A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism

Cancer results from disturbances of cellular signal transduction and data p rocessing at the genetic and epigenetic level. In the early phase of the di sease these disturbances are mainly caused by environmental toxic agents, i .e. genotoxic and non-genotoxic carcinogens, whereas endogenous agents deri ved from dys-regulated metabolic reactions may take over this role at later stages, thereby leading to a state of 'genetic instability' and 'growth au tonomy'. Among these metabolic reactions becoming dys-regulated in the cour se of tumorigenesis, eicosanoid biosynthesis from arachidonic acid seems to play a particular role. A steadily increasing body of evidence indicates a causal relationship between cancer development and an abnormal overexpress ion of eicosanoid-forming enzymes, i.e, cyclooxygenases and lipoxygenases, in a wide variety of human and animal tumors. This overexpression seems to result from disturbances of cellular signaling cascades such as the Ras-Raf -MAPkinase cascade due to oncogenic gene mutations. Presently, research is focussed on the proinflammatory enzyme cyclooxygenase-2 (COX-2) the patholo gical overexpression of which has been found to be related to key events of tumor promotion such as cellular hyperproliferation, inhibition of program med cell death, and tumor angiogenesis. In the mouse skin model of multista ge carcinogenesis COX-2-derived prostaglandin F-2 alpha has been indentifie d as an endogenous tumor promoter. Moreover, genotoxic byproducts of both c ylooxygenase and lipoxygenase-catalyzed arachidonic acid metabolism (such a s active oxygen species, free radicals etc.) are suspected to contribute to 'genetic instability' and thus to malignant progression of tumor cells. Th e enzymes of eicosanoid biosynthesis rank therefore among the most attracti ve targets for cancer chemoprevention. In fact, both nonsteroidal antiinfla mmatory drugs, i.e. non-specific COX inhibitors, and isozyme-specific COX-2 inhibitors have been shown to inhibit experimental and human cancer develo pment, in the latter case in particular in the large bowel. Beside their ro le as indicators of neoplastic development eicosanoids may be also used as reporters of skin irritation. Based to this concept an in vitro test system for skin toxicity has been developed in which the release of arachidonic a cid and interleukin-lcr, i.e. two key mediators of acute inflammation, from a human keratinocyte cell line is measured. The excellent correlation foun d between this mediator release and the effects of various chemical irritan ts on human skin in vivo indicates that, in the near future, this and relat ed methods may help to do without animal experiments in toxicological testi ng. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.