Recent Advances in Cyclooxygeneae-2 (Cox-2) Inhibitors: Novel Drugs for Rheumatoid Arthritis and Cancer

20 January, 2000

Recent Advances in Cyclooxygeneae-2 (Cox-2) Inhibitors: Novel Drugs for Rheumatoid Arthritis and Cancer

Prostaglandins are arachidonate metabolites produced in mammalian tissues, with diverse biologic effects including vasoconstriction, vasodilatation, stimulation or inhibition of platelet aggregation, and immunomodulation. They are also implicated in a variety of pathologic conditions such as inflammation and malignancy. Prostaglandin synthesis is mediated by two cyclooxygenase enzymes: cyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2). Cox-1 is constitutively expressed in many tissues and cytoprotective in the gastric mucosa endothelium, platelets and kidneys, and mediates production of gastrointestinal-protective (tract mucosal) prostaglandins. Cox-2 mediates production of prostaglandins responsible for pain, inflammation and fever, and is induced by diverse inflammatory stimulations.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase enzymes consequently to abolish the effects of prostaglandins. Commonly used NSAIDs inhibit both Cox-1 and Cox-2. These inhibitors are limited in use by toxicity to normal tissues, particularly by GI upset, ulcerations and bleeding in the gastrointestinal tract due to the inhibition of Cox-1. This gastrointestinal injury is a common outcome. Recently, compounds have been developed that are Cox-2 selective inhibitors and exert potent anti-inflammatory activity with few undesirable side effects. The comparison of the actions of over 40 conventional NSAIDs and new Cox-2 selective compounds showed a distribution of compound selectivities toward Cox-1 in enhancing the risk of serious gastrointestinal complications (Warner TD et al, 1999: uid=10377455). Thus Cox-2 selective compounds should be safer than those NSAIDs that were in common use in the past for treating arthritis and other inflammatory conditions, while reducing the adverse gastrointestinal effects.

For example, Cox-2 inhibitors are now viewed as potential drugs for treatment of rheumatoid arthritis, and Emery P et al (1999: uid=10609815) compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a Cox-2 selective inhibitor, with diclofenac, a non-specific Cox inhibitor in 655 patients with adult-onset rheumatoid arthritis of at least 6 month duration. Celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily were administered orally for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were examined every 4 weeks, and at week 24 safety was assessed endoscopically in the upper-gastrointestinal regions. showed anti-inflammatory and analgesic activity similar to diclofenac and a lower frequency of upper gastrointestinal ulceration (4 vs 15%) or gastrointestinal adverse events (6 vs 16%). The tolerability of celecoxib was better.

There have been a increasing number of Cox-2 selective compounds (e.g. celecoxib, rofecoxib, meloxicam, SC-236 and diisopropyl fluorophosphate) in line for drug development. An ingenious method is also applied to convert Cox-1 inhibiting NSAIDs to Cox-2 selective derivatives (Kalgutkar AS et al, 2000: uid=10639181). ETYA (5,8,11,14-eicosatetraynoic acid), arylacetic acid (e.g. indomethacin) and fenamic acid (e.g. meclofenamic acid) may be modified in carboxylate moiety to amide derivatives to generate potent and Cox-2 selective inhibitors. Selectivity of these derivatives seem to arise from novel interactions with the enzyme and molecularly differs from that of the parent NSAIDs.

Cox-2 is induced upon a variety of stimulations. It is induced in activated T lymphocytes, and inhibited by immunosuppressive cyclosporin A. Cox-2 selective inhibitors severely diminished early and late events of T cell activation, including CD25 and CD71 cell surface expression, IL-2, TNF-alpha, and IFN-gamma production and cell proliferation (Iniguez MA et al 1999: uid=10384106). These results indicate that COX-2 selective NSIADs are modulators of the immune activation.

Cox-2 is also induced in tumors. Cox-2 is highly expressed in colon cancers and adenomas, and the inhibition of this enzyme leads to apoptosis in colonic neoplasms. In fact, aspirin and other NSAIDs have been consistently associated with a reduced risk of colorectal cancer. An inverse association with adenomatous polyps was also seen with regular aspirin use. Regular aspirin use reduced the risk of colorectal cancer mortality by ca 50% and development of new colon polyps by up to 25%. . Sulindac was reported to induce regression of adenomas in patients with familial adenomatous polyposis, implicating the use to these compounds in the treatment of adenomatous colon polyps. In addition, an increasing number of reports show that NSAIDs (e.g. aspirin, indomethacin, sulindac, piroxicam and Cox-2 selective celecoxib) inhibit the development of cancer in both experimental animals and in humans, reduce the size of established tumors and increase the efficacy of cytotoxic anticancer agents (for reviews, Potter JD, 1999: uid=10359544; also Taketo MM, 1998: uid=9790545 and uid=9811310). Extensive clinical trials are now under way to establish Cox-2 inhibitors as anticancer drugs. In another interesting use, Cox-2 inhibitors have potential for improving the efficacy of radiotherapy since they prolong the delay of tumor growth after radiotherapy (Milas L et al, 1999: uid=10469752).

Cox-2 is low in unstimulated cells and highly expressed upon a variety of stimulations and carcinogenesis. It is a most promising target for novel drug development.

Related article: Drugs Emerging to Replace Aspirin and As Anti-Cancer Agents

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