ALIMENTARY TRACT:CLINICAL REVIEW Cyclo-Oxygenase Inhibition in Colorectal Adenomas and Cancer Paolo Ricchi, MD, PhD, Sandro Pignata, MD, PhD, Rosario Vincenzo Iaffaioli, MD, and Bruno Daniele, MD, PhD Abstract: Increasing evidence indicates that Non-steroidal anti- inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), can reduce the number and size of adenomas in patients with familial adenomatous polyposis as well as the incidence of colorectal cancer. The COX enzyme family consists of the classic COX-1 and a second enzyme, COX-2, which is induced by various stimuli, such as mitogens and cytokines. While it is well proven that COX-2 overexpression is a central event in colorectal carcinogenesis, that prostaglandins (PGs) can contribute to tumori- genesis, and that COX-2 selective inhibitors are active chemopreven- tive agents, the molecular mechanisms by which NSAIDs exert their chemopreventive effect is not fully understood. However, significant advances have been made in understanding the interference of NSAIDs with the pathways that control cell growth and survival even independently from their COX-inhibiting properties, making their use attractive both alone and in combination with standard therapies in the treatment of advanced colorectal cancer. In addition, the re- cently recognized anti-angiogenic and radiosensitizer properties of COX-2 inhibitors support, further suggest their use in the adjuvant setting. Key Words: FAP, COXs, chemoprevention (J Clin Gastroenterol 2003;37:281–287) C olorectal cancer is the third most common cancer in the world, and the second most common cause of cancer re- lated death. Similar to many cancers in humans, colorectal can- cer development is the result of a multistage and dynamic pro- cess called “multistep carcinogenesis” that involves the progressive accumulation of mutations and epigenetic abnor- malities in the expression of multiple genes. 1 During these consecutive series of stages called initiation, promotion, and progression, cells progressively acquire mutations and un- dergo genetic damage. Genetic, experimental and epidemio- logic studies indicate that colorectal cancer derives from com- plex interactions between inherited susceptibility and environ- mental factor, which participate to tumor genesis as initiating or promoting agents. The goal of chemoprevention is to reverse, suppress, or prevent the recurrence of cancer. Chemopreventive measures are especially important and reasonable in patients who carry an elevated risk for neoplasm caused by genetic or environ- mental factors; on the other hand, in general population they must be particularly well tolerated and must have a favorable risk-to-benefit ratio, because of the lower frequency of colo- rectal cancer. Epidemiologic studies have shown that NSAIDs are chemopreventive agents when assumed for a long period. Most of the studies (reviewed by Kubba 2 ) provided substantial evidence that exposure to aspirin and other NSAIDs, was as- sociated with a reduced risk for developing colon cancer in general population. Non-steroidal anti-inflammatory drugs are a class of compounds that share the property of inhibiting the enzymatic activity of cyclooxygenase (COX). Cyclooxygen- ase is the rate-limiting enzyme for the synthesis of eicosanoids, such as prostaglandins, from arachidonic acid. Two isoforms of COX have been identified: constitutively expressed cyclo- oxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2). Cyclooxygenase-1 is a housekeeping gene and has an important role in protecting the gastroduodenal mucosa. The COX-2 gene, an immediate early-response gene, is rapidly induced in response to tumor promoters, cytokines, and growth factors. 3–7 Non-steroidal anti-inflammatory drugs may have different ability to inhibit COX-1 and COX-2; based on this effect, they can be basically grouped into selective and non- selective inhibitors of COX-2 (reviewed by Taketo et al). 8 The majority of past epidemiologic studies were per- formed with aspirin and older conventional NSAIDs, which inhibited both COX-1 and COX-2 non-selectively and caused Received for publication March 27, 2002; accepted June 3, 2003. From the Department of Biologia e Patologia Cellulare e Molecolare “L. Califano”, Centro di Endocrinologia ed Oncologia Sperimentale “G. Salvatore” del Consiglio Nazionale delle Ricerche, Universita ` “Federico II”, Napoli, 80131 Italy (Dr Ricchi), and the Division of Oncologia Medica B, Istituto Nazionale Tumori, Fondazione G. Pascale, Napoli, Italy (Drs Ricchi, Pignata, Iaffaioli and Daniele). Reprints: Dr. Bruno Daniele, Division of Oncologia Medica B, Istituto Nazio- nale Tumori, Fondazione G. Pascale, Napoli, Italy via M. Semmola 5, 80131 Napoli Italy (e-mail: b.daniele@libero.it). Copyright © 2003 By Lippincott Williams & Wilkins J Clin Gastroenterol • Volume 37, Number 4, October 2003 281