ReviewCelecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention
Introduction
Since the discovery and introduction of aspirin a little more than a century ago, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) have become the most widely used therapeutic agents in the treatment of pain, inflammation and fever all over the world. Although primarily used to treat pain and inflammation associated with arthritis, NSAIDs may also have a role in the management of different conditions such as cancer prevention, Alzheimer’s disease and prophylaxis against cardiovascular disease [1].
Despite the wide use of NSAIDs over the last century, the principal mechanism of action of these drugs was not discovered until 1971. In 1971, Vane [2] reported that the ability of NSAIDs to suppress inflammation rested primarily on their ability to inhibit the cyclooxygenase enzyme.
Prostaglandins (PGs) are short-living substances acting as local hormones (or autacoids) and are important in normal physiology as well as in some pathologic conditions [3]. In humans, PGs are involved in diverse functions, including blood clotting, ovulation, initiation of labor, bone metabolism, nerve growth and development, wound healing, kidney function, blood vessel tone, immune responses and protection of gastroduodenal mucosa. PGs are synthesized in a broad range of tissue types and serve as autocrine or paracrine mediators to signal changes within the immediate environment [1].
NSAIDs act primarily by inhibiting COX, thereby blocking the formation of PG in normal and inflamed tissues. Until the mid-1980s, it was thought that the formation of PG was limited solely by the availability of the substrate arachidonic acid, but data obtained by Needleman et al. [3] indicated that the amount of COX enzyme was substantially increased in inflamed tissues. This finding led to the identification of a new COX isoform. Although both COX isoenzymes perform the same catalytic activity on the same substrates and are about 60% homologous, they differ in regulation, distribution and expression [4].
NSAIDs are a heterogeneous group of chemically unrelated compounds with similar therapeutic effects, i.e., anti-inflammatory, analgesic and antipyretic effects [5]. However, NSAIDs are associated with serious side effects, the most significant of which are related to the gastrointestinal (GI) system. NSAID related GI complications probably account for the largest number of deaths attributable to any class of therapeutic agent. The Food and Drug Administration (FDA) in the United States is estimated that ulcers and serious ulcer complications, such as bleeding and perforation occur at the rate of 2–4% per year in chronic NSAID users. It is estimated that 107,000 patients in the United States are hospitalized annually for NSAID related GI complications and at least 16,500 NSAID related deaths occur each year among arthritis patients alone. Serious NSAID associated complications frequently occur without warning symptoms [6].
Based on the discovery of COX-2 enzyme, it was proposed that a selective inhibitor of COX-2 would be an attractive approach to the treatment of inflammatory conditions, without the side effects of gastric and renal toxicity and inhibition of platelet function [7].
In this article, we reviewed pharmacological properties and cancer preventive effects of a COX-2 inhibitor, celecoxib.
Section snippets
Methodology
The literature search was based on Medline (direct online) and reference lists in published papers; then the hand search of relevant papers. Key words used for database search included “celecoxib” and “cancer prevention”.
By the search methods, 240 papers were identified and 168 of them were selected for review. Included papers have been published between 1971 and 2003.
Results
The present review is composed of two main parts. In the first part, pharmacokinetic and clinical studies of celecoxib were reviewed. In the second part, chemo-preventive effects of celecoxib were investigated and discussed.
Pharmacokinetic and clinical studies were concluded the dosage, tolerability, analgesic efficacy, drug interactions and the side effects of celecoxib. Some of these studies were compared celecoxib with other NSAIDs. The large outcome study, the Celecoxib Long-Term Arthritis
Discussion
NSAIDs are the most widely used therapeutic agents in the treatment of pain, inflammation and fever all over the world. NSAIDs may also have a role in the management of cancer prevention, Alzheimer’s disease and prophylaxis against cardiovascular disease [1]. NSAIDs act by reducing prostaglandin synthesis through the inhibition of COX. This enzyme has two isoforms, COX-1 and COX-2 [2]. Although both COX isoenzymes perform the same catalytic activity on the same substrates and are about 60%
Acknowledgements
The authors thank Mrs. Aytül Develi from Department of Foreign Languages, Hacettepe University for the edition of this manuscript.
References (168)
COX-2 inhibitors
Lancet
(1999)First COX-2 inhibitor clears initial FDA hurdle (news: science and medicine)
Lancet
(1998)- et al.
Colorectal cancer and non-steroidal anti-inflammatory drugs
Adv. Pharmacol.
(1997) - et al.
Rectal proliferation and polyp occurrence in patients with familial adenomatous polyposis after sulindac treatment
Gastroenterology
(1994) - et al.
Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas
Gastroenterology
(1994) - et al.
Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors
Gastroenterology
(1996) - et al.
Elevated cyclooxygenase-2 levels in Min mouse adenomas
Gastroenterology
(1996) - et al.
Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase-2 (COX-2)
Cell
(1996) - et al.
The effect of selective cyclooxygenase inhibitors on intestinal epithelial cell mitogenesis
J. Surg. Res.
(1999) - et al.
Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells
Hepatology
(2002)