Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer.
Members of the structurally diverse class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs) have the ability to prevent or reduce the occurrence of colorectal, certain other gastrointestinal, and perhaps other cancers. The anticarcinogenic property of NSAIDs has been shown in epidemiological studies with humans and in experimental carcinogenesis studies with animals. In addition, clinical studies of the human disease familial adenomatous polyposis have demonstrated the efficacy of NSAIDs in mediating regression of colorectal adenomas. The mechanism of the anticarcinogenic effect of these drugs is not known, but most hypotheses have involved the common property of the NSAIDs to inhibit prostaglandin synthase (PHS) enzymes and thereby cause a subsequent reduction in levels of prostaglandins (PG) in tissue. Recent reports have questioned the role of PHS inhibition in the anticarcinogenic activity of NSAIDs by showing that some NSAID-related compounds that are not PHS inhibitors can induce the same anticarcinogenic changes in cell cycle and apoptotic response as the PHS inhibitors. In this review we will examine the evidence that NSAIDs are anticarcinogenic, the evidence supporting PHS as the target of NSAIDs, and the evidence for and against inhibition of PG synthesis as the mechanism of cancer prevention by NSAIDs.
Levy
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Department of Pharmacology, University of Michigan, Ann Arbor 48109-0632, USA.
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001095:Arachidonic Acids / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin