Cyclooxygenase inhibitors: Scope of their use and development in cancer chemotherapy

The traditional nonsteroidal anti‐inflammatory drugs (NSAIDs) exert their effect by inhibition of cyclooxygenase‐1 (COX‐1) as well as COX‐2 enzymes. As COX‐1 is responsible for maintaining normal biological functions, the nonselective inhibition of these enzymes caused side effects including gastrointestinal (GI) problems. Recently developed selective COX‐2 inhibitors could reduce these adverse effects, but the evidence of cardiovascular side effects including an increased risk of myocardial infarction began to emerge, and some of the COX‐2 inhibitors were eventually withdrawn from the market and this led to the downfall of this research. So, the discovery of novel COX‐2 inhibitors with their safety profile became the biggest challenge in pharmaceutical research. However, recent mechanistic and clinical studies revolutionized this area by indicating the fact that COX‐2 is involved in apoptosis resistance, angiogenesis, and tumor progression. Epidemiological data suggest that selective COX‐2 inhibitors might prevent the development of cancers. Moreover, COX‐2 is found to be overexpressed in many cancers thus making it an attractive therapeutic target for the prevention and treatment of a number of malignancies. The purpose of this review is to focus on the medicinal chemistry aspects of COX‐2 inhibitors in cancer chemotherapy and recent reports on these inhibitors as anticancer agents. We attempted to cover only the COX inhibitors that showed anticancer activity, although a number of potent COX‐2 inhibitors have been reported without their anticancer effects. Furthermore, structure–activity relationships (SAR) of different classes of compounds for COX‐2 inhibition as well as anticancer activity, and their future applications are discussed. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 2, 161–201, 2011     

Are COX‐2 inhibitors preferable to combined NSAID and PPI in countries with moderate health service expenditures?

Rationale In developed countries, cyclooxygenase 2 (COX‐2) inhibitors were shown to be less costly than the combination of non‐steroidal anti‐inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) in treatment of patients with high risk of serious gastrointestinal (GI) adverse effects. It is questionable if such results apply to developing countries where health service costs are lower and there is high discrepancy between generic and patent protected drug prices. We analysed the direct cost of treatment with generic NSAIDs in combination with PPIs versus branded COX‐2 inhibitors in patients with high risk of serious GI adverse effects from the perspective of the public health service in Serbia. Methods Total cost of treatment of serious GI complications and the use of NSAID+PPI versus COX‐2 inhibitors were calculated. A model for estimation of cost of treatment of NSAID+PPI versus COX‐2 inhibitors which included the probability of developing serious GI adverse effects was developed. Results Total cost of treatment of serious GI adverse effects resulted in an average of $814/patient. Considering the relative risk of such adverse effects for patients with four or more risk factors, the least costly treatment over 6 months was the use of celecoxib ($487). Compared with diclofenac+omeprazole, cost savings were estimated at $59 and $22 per patient with celecoxib and etoricoxib, respectively. Conclusion Cost savings may be achieved by using COX‐2 inhibitors in patients at high risk of GI adverse effects even in countries with moderate health care service expenditures. Such possibility requires further investigation.     

Development and clinical application of COX-2-selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis

Osteoarthritis (OA) and rheumatoid arthritis (RA) are among the most prevalent chronic illnesses and leading causes of disability in the United States. The clinical symptoms of OA and RA, pain and inflammation, are biologic processes mediated in part by prostanoids-prostaglandins, prostacyclin, and thromboxanes. The intermediate enzymes responsible for prostaglandin biosynthesis, cyclooxygenase (COX)-1 and COX-2, have been the target of arthritis therapy using nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). An understanding of the biochemistry and molecular pharmacology of COX enzymes has allowed for the development of agents that specifically inhibit COX-2. COX-2-selective inhibitors have efficacy in OA and RA that is similar to that of NSAIDs but with a lower potential for upper gastrointestinal injury, a serious side effect of nonselective NSAIDs. COX-2-selective inhibitors have been increasingly used in the treatment of OA and RA as well as other inflammatory arthropathies including ankylosing spondylitis and gout. Clinical trials with two currently available drugs, rofecoxib and celecoxib, have demonstrated efficacy comparable to nonselective NSAIDs but with a lower risk of gastrointestinal side effects. In general, these drugs are well tolerated in patients with aspirin-sensitive asthma. Rofecoxib is well tolerated in patients with sulfonamide sensitivities; further studies are needed to fully characterize the utility of celecoxib in these patients. Clinical experience shows that because of their improved GI safety, rofecoxib and celecoxib, and newer COX-2-selective inhibitors (valdecoxib, etoricoxib, parecoxib), represent a significant advance in the treatment of arthritis and other related inflammatory conditions.     

Non steroidal anti‐inflammatory drugs and COX‐2 inhibitors as anti‐cancer therapeutics: hypes,hopes and reality

Non‐steroidal anti‐inflammatory drugs (NSAIDs) and specific inhibitors of cyclooxygenase (COX)‐2, are therapeutic groups widely used for the treatment of pain, inflammation and fever. There is growing experimental and clinical evidence indicating NSAIDs and COX‐2 inhibitors also have anti‐cancer activity. Epidemiological studies have shown that regular use of Aspirin and other NSAIDs reduces the risk of developing cancer, in particular of the colon. Molecular pathology studies have revealed that COX‐2 is expressed by cancer cells and cells of the tumor stroma during tumor progression and in response to chemotherapy or radiotherapy. Experimental studies have demonstrated that COX‐2 over expression promotes tumorigenesis, and that NSAIDs and COX‐2 inhibitors suppress tumorigenesis and tumor progression. Clinical trials have shown that NSAIDs and COX‐2 inhibitors suppress colon polyp formation and malignant progression in patients with familial adenomatous polyposis (FAP) syndrome. Recent advances in the understanding of the cellular and molecular mechanisms of the anti‐cancer effects of NSAIDs and COX‐2 inhibitors have demonstrated that these drugs target both tumor cells and the tumor vasculature. The therapeutic benefits of COX‐2 inhibitors in the treatment of human cancer in combination with chemotherapy or radiotherapy are currently being tested in clinical trials. In this article we will review recent advances in the understanding of the anti‐tumor mechanisms of these drugs and discuss their potential application in clinical oncology.     

Prevention of anti‐inflammatory drug‐induced gastrointestinal damage: Benefits and risks of therapeutic strategies

Patients who take non‐steroidal anti‐inflammatory drugs (NSAIDs) may develop serious gastrointestinal (GI) side effects in both the upper and lower GI tract. Those at risk should be considered for prevention with misoprostol, proton pump inhibitor (PPI) or COX‐2 selective inhibitor (coxib) therapy. A coxib or an NSAID+PPI combination is considered to have comparable GI safety profiles, but evidence from direct comparison is limited. PPIs are effective in the prevention of upper GI events in endoscopy trials and in a few, small, outcome trials in patients at risk. Coxibs have been evaluated in endoscopic ulcer studies and clinical outcome trials, and shown to significantly reduce the risk of upper GI ulcer and complications. Moreover, unlike PPIs, coxibs significantly reduce toxicity in the lower GI tract compared with NSAIDs. Coxibs and possibly some NSAIDs also increase the risk of developing serious cardiovascular events, an effect which may depend on the drug, dose and duration of therapy. It is not known whether concomitant low‐dose aspirin use, which occurs in more than 20% of patients, will reduce the incidence of cardiovascular events, although concomitant aspirin increases the risk of developing serious GI events in patients taking either an NSAID or a coxib. Such patients may require additional PPI co‐therapy. Current prevention strategies with an NSAID+PPI, misoprostol or a coxib must be considered in the individual patient with GI and cardiovascular risk factors. A PPI+coxib is indicated in those at highest risk (e.g. previous ulcer bleeding). PPI therapy must be considered for the treatment and prevention of NSAID‐induced dyspepsia.     

Development of anti-inflammatory drugs targeted against prostaglandin-related molecules

Prostaglandin E2 (PGE2) is a proinflammatory mediator that is synthesized by cyclooxygenases (COX-1 and COX-2) and prostaglandin E synthases (cPGES-1 and mPGES-1); PGE2 exerts its biological effects by binding to specific receptors. Although non-steroidal anti-inflammatory drugs(NSAIDs), which are non-selective COX inhibitors, have been very often used as painkillers, their side effects such as gastrointestinal hemorrhage remain a serious problem. Therefore, the selective COX-2 inhibitors were developed; the use of these inhibitors exerted anti-inflammatory effects without the increased risk of gastrointestinal events. Unfortunately, however, several clinical studies demonstrated that the inhibition of COX-2 was associated with the increased risk of cardiovascular events. Consequently, mPGES-1 and PGE2 receptors are currently expected to be attractive targets for anti-inflammatory drug development in order to reduce the side effects.     

The choice of selective COX-2 inhibitors

Non-steroidal anti-inflammatory drug (NSAID) has been widely prescribed as a useful antifebrile or painkiller. But, gastrointestinal injury as a side effect of NSAIDs has been a big social probrem. NSAID-induced gastric damage has been shown to be induced by the inhibition of both cyclooxygenase (COX)-1 and 2. Thus, selective COX-2 inhibitors are expected to induce less gastric injury and to be safe as compared to traditional NSAIDs. But in certain situations such as gastric ulcer or H. pylori-induced gastritis, selective COX-2 inhibitors may delay ulcer healing or repair processes. Previous reports have shown that COX-2 inhibitors increase cardiovascular (CV) events as compared with placebo and recent studies further suggest that all NSAIDs might also be involved in increases in CV events. Therefore, any NSAIDs must be carefully used when they are prescribed for patients with CV risks.     

Selective cyclooxygenase-2 inhibitors for the treatment of arthritis.

The purpose of this paper is to review the rationale for a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) known as selective cyclooxygenase (COX)-2 inhibitors and to present preliminary clinical data on 2 COX-2 inhibitors that are approved for use in the United States. The primary mechanism of NSAIDs in the treatment of inflammation is the inhibition of COX, which exists in 2 forms. COX-I appears to regulate many normal physiologic functions, and COX-2 mediates the inflammatory response. Theoretically, an NSAID that inhibits COX-2 selectively should decrease inflammation but not influence normal physiologic functions and thus should cause fewer gastrointestinal side effects. Preliminary data suggest that celecoxib, a highly selective COX-2 inhibitor, is superior to placebo and similar to traditional NSAIDs in the short-term treatment of pain due to osteoarthritis, although it has been associated with adverse effects such as headache, change in bowel habits, abdominal discomfort, and dizziness. Celecoxib also has been shown to be as effective as traditional NSAIDs in the treatment of rheumatoid arthritis, but it may cause fewer adverse effects, including endoscopically documented ulcers. Celecoxib is metabolized in the liver by the cytochrome P-450 isozyme CYP2C9, and thus serious drug interactions are possible. In the treatment of osteoarthritis, rofecoxib has been shown to be as effective as traditional NSAIDs and may cause fewer endoscopically documented ulcers, but its complete adverse-effect profile is not known. Until the selective COX-2 inhibitors are widely used and more clinical as well as pharmacoeconomic studies are published, the exact role of COX-2 therapy cannot be determined. words: cyclooxygenase, celecoxib, rofecoxib, rheumatoid arthritis, osteoarthritis.     

A Critical Appraisal of COX‐2 Selective Inhibition and Analgesia: How Good So Far?

Abstract: The development of COX‐2 selective inhibitors has opened a new era of clinical investigation in NSAIDs. Discussion of the established concepts of inflammation and therapeutical uses of these drugs has changed the rationale for its clinical use and therapeutic labeling of these drugs. A comprehensive discussion across basic science and clinical areas involved in each of these concepts is presented. This led to a remarkable re‐evaluation of our insights on their traditionally proposed mechanisms of analgesia, their side‐effects, and the clinical indication of NSAIDs as “over the counter” pain killers. This may shift physicians toward a more rational use of this drug class.     

Cardiovascular risk,hypertension, and NSAIDs

During the past 2 years, a great deal of evaluation has been conducted on the cardiovascular (CV) effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors. This review focuses on the effects of the NSAIDs and COX-2 inhibitors on blood pressure and CV events. Clinical trial databases for NSAIDs and COX-2 inhibitors have shown varying levels of destabilization of blood pressure control in treated hypertensive patients as well as variable incident rates of the development of arrhythmias, congestive heart failure, myocardial infarction, and stroke. Nonselective and COX-2 selective NSAIDs can be used carefully in arthritis patients with hypertension and stable CV disorders (excluding congestive heart failure and moderate to severe kidney dysfunction) when the individual clinical benefit of anti-inflammatory therapy outweighs the CV and gastrointestinal risk.     

Gastrointestinal safety and tolerability of nonselective nonsteroidal anti-inflammatory agents and cyclooxygenase-2-selective inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used of all drugs and are the most common medications used by persons aged 65 years or more. NSAIDs have a number of side effects, of which the most prevalent and serious is gastrointestinal (GI) toxicity. GI side effects of NSAIDs range from dyspepsia and gastroduodenal ulcers to serious, potentially fatal GI complications including bleeding and perforation. Serious GI complications often lack warning signs; knowledge of risk factors for NSAID-related gastropathy can identify patients at high risk, allowing for initiation of the appropriate therapeutic intervention. Risk factors include advanced age, NSAID dose, prior GI complications, infection with Helicobacter pylori, and use of corticosteroids and anticoagulants. There are few well-established strategies to prevent GI complications in NSAID users. Risk assessment and cotherapy with acid suppressors (H2-receptor antagonists and proton pump inhibitors) or prostaglandin replacement (misoprostol) and H pylori eradication are beneficial. Cyclooxygenase-1 (COX-1) is a key enzyme in gastroprotective mucosal defenses, and the best way to prevent GI toxicity is to avoid drugs that inhibit COX-1. Clinical studies of the COX-2-selective inhibitors rofecoxib and celecoxib have demonstrated efficacy equivalent to nonselective NSAIDs with lower rates of GI side effects (for example, incidence of endoscopic ulcers equivalent to placebo). Selective COX-2 inhibitors (coxibs) provide effective treatment of pain and inflammation while reducing risk of gastropathy.     

Can COX-2 selective inhibitor prevent NSAIDs-related GI toxicity?

The gastrointestinal (GI) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is well recognized. Risk factors for NSAIDs-related GI toxicity includes advanced age, generalized disease, past history of peptic ulcer, concomitant use of steroid, duplicated use of various NSAIDs. The guidelines recommended using a proton pump inhibitor or a prostaglandin for the treatment and prevention of NSAIDs-related GI toxicity. The updated guideline added cyclooxygenase-2 (COX-2) selective inhibitors, which have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain, to the prevention strategy. Several large, randomized, clinical trials compared the rates of serious GI events in patients taking COX-2 selective inhibitors and nonspecific NSAIDs but came to different conclusions. More recently, the overall safety profile of COX-2 selective inhibitors and traditional NSAIDs has come under intense debate especially due to the recently shown cardiovascular risk of COX-2 selective inhibitors. Therefore, it is essential to determine the actual risk of GI toxicity with COX-2 selective and traditional NSAIDs alone or combined with other compounds from independent Japan studies.     

Selective cyclooxygenase inhibition: its role in pain and anaesthesia.

Cyclooxygenase inhibitors reduce inflammation and hyperalgesia by decreasing prostaglandin E2 production. Traditional NSAIDs (inhibiting both COX-1 and 2) though ubiquitous in peri-operative pain practice, have well-known gastrointestinal (GI), cardiovascular and other risks. This article systematically addresses the main efficacy and safety issues pertaining to NSAID and selective COX-2 inhibitors (coxibs) use, focusing on the acute pain context, particularly post-operative pain management. NSAIDs and coxibs are of proven analgesic efficacy in post-operative pain control, and their opioid-sparing role in multimodal analgesia, leads to significantly reduced opioid related side effects. Although GI risk is regarded as less of an issue in short-term therapy, in patients with a past history of peptic ulceration who are denied NSAIDs, coxibs may be considered a suitable alternative. In the peri-operative setting, coxibs confer an additional advantage over NSAIDs by preserving the platelet thromboxane production and clotting. Cardiovascular safety has been assessed for the parenteral parecoxib and its active moiety valdecoxib, and was found to be satisfactory in major non-cardiac surgery, but increased thromboembolic complications occurred in coronary artery bypass surgery leading to contra-indication for this type of surgery. Coxibs and NSAIDs have similar renal effects and caution or avoidance is required with renal disease or reduced peri-operative renal perfusion. Coxibs may be safer in aspirin-sensitive asthmatics. Bone healing effects remain controversial, but only a few days therapy appears to be safe.     

An evidence-based update on nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. NSAIDs are a necessary choice in pain management because of the integrated role of the COX pathway in the generation of inflammation and in the biochemical recognition of pain. This group of drugs has recently come under scrutiny because of recent focus in the literature on the various adverse effects that can occur when applying NSAIDs. This review will provide an educational update on the current evidence of the efficacy and adverse effects of NSAIDs. It aims to answer the following questions: (1) are there clinically important differences in the efficacy and safety between the different NSAIDs, (2) if there are differences, which are the ones that are more effective and associated with fewer adverse effects, and (3) which are the effective therapeutic approaches that could reduce the adverse effects of NSAIDs. Finally, an algorithm is proposed which delineates a general decision-making tree to select the most appropriate analgesic for an individual patient based on the evidence reviewed.     

Recent development of selective cyclooxygenase-2 inhibitors

Nonsteroidal anti-inflammatory drugs(NSAIDs) are clinically effective against the inflammatory symptoms of rheumatoid arthritis. Recent attention has been focused on selective cyclooxygenase(COX)-2 inhibitors, a type of NSAID that inhibits a subtype of COX. Because of the different actions of COX-1 and COX-2, selective COX-2 inhibitors were expected to reduce adverse reactions such as gastrointestinal disorders. Various clinical studies have confirmed that the efficacy of COX-2 inhibitors for RA is similar to that of conventional NSAIDs, but they cause fewer severe gastrointestinal disorders. The incidence of complications related to renal dysfunction, such as edema and hypertension, is not different. Patients using selective COX-2 inhibitors have recently been reported to show an increase in thrombotic complications such as myocardial infarction. Therefore, more data on adverse events should be collected in the future from large-scale clinical studies to further clarify the actual value of selective COX-2 inhibitors.     

The cyclooxygenase-2 inhibitors: safety and effectiveness.

OBJECTIVE: To review the development of cyclooxygenase-2 (COX-2) inhibitors and discuss specific agents that are currently under investigation or have been marketed. DATA SOURCES: Primary literature on selective COX inhibitors was identified from a comprehensive MEDLINE, English-literature search from January 1966 through September 1998, with additional studies selected by review of the references. Abstracts from recent meetings and package insert literature from approved agents were also used as source material. Indexing terms included COX-2 inhibitors, meloxicam, celecoxib, rofecoxib, flosulide, SC-58635, and MK-966. STUDY SELECTION: Human clinical, pharmacokinetic, and dose-ranging trials performed in Europe and the US and randomized comparative trials were reviewed. DATA SYNTHESIS: With the discovery of at least two COX isoforms, a better understanding of the mechanism of action and gastrointestinal toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) has been realized. While COX-1 is involved in physiologic maintenance, COX-2 seems to be involved in inflammation, mitogenesis, and specialized signal transductions. Selective COX-2 inhibitors may allow maximum antiinflammatory activity while improving the safety profile associated with NSAID therapy. Celecoxib and rofecoxib have been approved by the Food and Drug Administration for the treatment of osteo- and rheumatoid arthritis; meloxicam is undergoing Phase III clinical trials. Preliminary data indicate that the selective COX-2 inhibitors provide analgesic and antiinflammatory efficacy comparable with older NSAIDs, with fewer adverse gastrointestinal effects. CONCLUSIONS: Specific COX-2 inhibitors offer promising benefits over older NSAIDs with regard to gastrointestinal safety while maintaining analgesic and antiinflammatory efficacy. Further study is required to determine long-term efficacy and safety in clinical use.     

Developing an economic rationale for the use of selective COX-2 inhibitors for patients at risk for NSAID gastropathy

Arthritis causes considerable patient morbidity and substantial health care resource utilization. One important contributing component to the overall cost burden of this condition is the variety of expenditures attributable to the adverse effects of arthritis therapy. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of medical treatment for patients with arthritis because of their well-established anti-inflammatory and analgesic effects. Generally well tolerated, traditional NSAIDs nevertheless cause adverse gastrointestinal (GI) effects in a proportion of patients. Because nonselective NSAIDs are so widely used, these GI adverse events cause significant morbidity and mortality, accounting for substantial additional health care expenditures. Data from controlled investigations document the enhanced GI safety of cyclooxygenase (COX)-2-selective inhibitors, or coxibs, when compared with nonselective NSAIDs. As a result of this improved safety profile, patients treated with coxibs use significantly fewer GI-related health care resources (eg, medications, procedures) than patients treated with nonselective NSAIDs. Thus, available clinical and economic data suggest that the use of coxibs has the potential to result in important clinical GI benefits at an acceptable incremental cost for all chronic NSAID users. For individuals who are at an increased risk of developing GI complications attributable to NSAIDs, coxibs are clearly a cost-effective treatment option.     

Selective COX-2 inhibitors and the surgical patient.

The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development (Golden & Abramson, 1999). Clinical studies thus far have established that the selective COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx) are effective in the treatment of OA and RA, as are conventional NSAIDs. However, they do not cause the same adverse effects on the GI mucosa nor do they increase bleeding time as do conventional NSAIDs. Therefore, their use is not contraindicated in pre or postsurgical patients. Further investigation is underway to fully elucidate the role of COX-2 and to determine any additional benefits of selective COX-2 inhibition.     

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

The efficacy of nonsteroidal anti‐inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long‐term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX‐2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine‐associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti‐inflammatory therapy.