Aspirin and the potential role of prostaglandins in colon cancer.

The arachidonic acid cascade generates a family of bioactive lipids that modulate diverse physiological and pathophysiological responses. Although there has been a great deal of interest in the involvement of arachidonic acid metabolites in cancer, there is uncertainty about which metabolites are the most im portant and how they contribute to specific steps in cell trans formation, tumor growth, and metastasis (1-9). The complex ity of arachidonic acid metabolism is daunting to neophytes and the multiplicity of responses exerted by a single metabolite can be confusing to the cognoscenti. This has made it difficult to extrapolate results from animal experiments to human beings. A recent report from Thun et al. (10) and previous reports from Rune et al. (11) and Rosenberg et al. (12) suggest that aspirin intake may reduce colon cancer incidence (11, 12) and mortality (10) in the general population. Other studies from Paganini-Hill et al. (13, 14) do not support such an association. Aspirin is a relatively specific inhibitor of one branch of the arachidonic acid cascade and even though there is not universal agreement among these epidemiological investigations, their findings refocus attention on the role of arachidonic acid me tabolites in cancer. This Perspective was written to highlight some of the existing literature on the aspirin-inhibitable branch of the arachidonic acid cascade and cancer, to apply that liter ature to colon cancer where possible, and to identify deficien cies in our knowledge that need to be addressed. Although the major focus is the colon, the mechanistic concepts should be applicable to other organ sites. The Perspective begins with an overview of arachidonic acid metabolism, proceeds to a consideration of the biochemistry and molecular biology of the enzyme inhibited by aspirin, touches on the signal transduction pathways linked to arachi donic acid metabolism, and then considers mechanisms by which specific arachidonic acid metabolites participate in the carcinogenic process. The review is not meant to be compre hensive and apologies are made in advance to colleagues whose work is not highlighted or was inadvertantly omitted.