Cyclooxygenase 2 selective inhibitors in cancer treatment and prevention

Abstract

Prostaglandin synthesis by a number of enzymes is important at all stages during the genesis of cancer. The availability of prostaglandin H(2) as a substrate for prostaglandin production is a critical control point in its synthesis. Cyclooxygenase (COX) occurs in two forms (COX-1 and -2) and acts as the rate-limiting enzyme that generates prostaglandin H(2). COX-1 is produced as a steady-state enzyme, while COX-2 is heavily involved in inflammation and tumorigenesis. Differences in the catalytic sites of these enzymes are utilised to generate COX-2 selective inhibitors. Certain chemical characteristics of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors make some of these inhibitors more effective against COX-2 than others. Epidemiological, animal and preclinical data demonstrate the promise of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors as anticancer agents. Ongoing clinical trials are designed to determine the efficacy of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors in the prevention and treatment of many types of cancer.

A critical role of COX-2 in the progression of neointimal formation after wire injury in mice

“…However, COX-2 is induced at sites of inflammation in response to growth factors and inflammatory cytokines [4][5][6][7][8]. COX-2 is a key factor in the progression of inflammation [9][10][11] and several clinical diseases [12,13]. Inflammation in response to vascular injury is becoming increasingly known as a possible mediator for intimal hyperplasia.…”

An Anacardiaceae preparation reduces the expression of inflammation-related genes in murine macrophages

“…COX occurs in two forms (COX-1 and -2) and is the rate-limiting enzyme in the generation of prostaglandin H (2). COX-1 is produced as a steady-state enzyme, while COX-2 is involved in inflammation and tumorigenesis [7]. Several studies have focused on the role of NO and proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-12, tumor necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-g) in the expression and/or activity of the inducible form of COX (COX-2), in a number of cell types including macrophages [8].…”

COX-2 Selective Inhibitors, Carbonic Anhydrase Inhibition and Anticancer Properties of Sulfonamides Belonging to This Class of Pharmacological Agents

“…One should stress that in the last 5 years, three compounds of those mentioned above became available clinically -rofecoxib 3, celecoxib 6 and valdecoxib 7 -and that they tend to replace the classical NSAIDs for many therapeutic uses [1,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]22]. …”

“…Thus, in the last several years COX-2 specific inhibitors have been developed that do not show the gastro-intestinal side-effects of classical non-steroidal antiinflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2 isozymes [4][5][6]. Whereas the anti-inflammatory effects of these new drugs can easily be explained taken into consideration their strong affinity for the above-mentioned COX isozyme [1,2], some recent reports dealing with the strong antitumour activity of several such drugs [7][8][9][10][11][12][13][14][15][16][17][18][19] offered only hypothesis for explaining this rather unexpected pharmacological profile. The recent report of the potent inhibition of several carbonic anhydrase (CA, EC 4.2.1.1) isozymes with the sulfonamide COX-2 selective inhibitors, and the determination of the X-ray crystal structures for the adducts of celecoxib and valdecoxib -two clinically used such drugs -with isozyme CA II [20] allow us to interpret the antitumour data of these compounds in an entirely different manner.…”