COX-2 inhibitor

COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug (NSAID) that directly targets COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. COX-2 selectivity does not seem to reduce other adverse effects of NSAIDs (most notably an increased risk of renal failure), and some results have shown an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib (commonly known as Vioxx) was taken off the market in 2004 because of these concerns.

Research history

For more details on this topic, see Discovery and development of cyclooxygenase 2 inhibitors.

The mouse COX-2 gene was cloned by UCLA scientist Dr. Harvey Herschman.^[1] The enzyme was discovered in 1988 by Daniel Simmons, a Brigham Young University researcher formerly of Harvard University.^[2] Dr. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, he had his notebook notarized as proof of his discovery. Subsequently, Pfizer, the research firm with whom Simmons had contracted, allegedly broke contract and refused to give Simmons any royalties and profits from his discovery. As of September 2010^[update], a lawsuit is in progress by Simmons against the drug developers.^[3][4]

In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme involved in their biosynthesis, cyclooxygenase.

Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain.

The existing non-steroidal anti-inflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin and ibuprofen are equipotent at inhibiting COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications.

A search for COX-2-specific inhibitors resulted in promising candidates such as valdecoxib, celecoxib, etoricoxib and rofecoxib (marketed under the brand names Bextra, Celebrex, Arcoxia and Vioxx respectively). Valdecoxib and rofecoxib are about 300 times more potent at inhibiting COX-2, than COX-1, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such adverse effects previously or had comorbidities that could lead to such complications. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1, with etoricoxib being 106 times more potent.

Although individual reactions to particular NSAIDs vary, in general the efficacy of COX-2 inhibitors has proved similar to that of other NSAIDs, as expected since both classes of drug inhibit the desired target, the action of COX-2 prostaglandins. The drugs effectiveness is similar to that of traditional NSAIDs such as ibuprofen, diclofenac, or naproxen.

Adverse effects

On September 27, 2004 Vioxx (Rofecoxib) was withdrawn voluntarily from the market, due to an increased risk of myocardial infarction and stroke. At present it is unclear whether this adverse drug reaction pertains also to other drugs of this group or is specific for rofecoxib.

Early COX-2-inhibiting drugs

Celebrex and celebra were introduced in 1999 and rapidly became the most frequently prescribed new drugs in the United States. By October 2000, their US sales exceeded 100 million prescriptions per year for $3 billion, and were still rising, sales of Celebrex alone reaching $3.1 billion in 2001. A Spanish study found that between January 2000 and June 2001, 7% of NSAID prescriptions and 29% of NSAID expenditures were for COX-2 inhibitors. Over the period of the study, COX-2 inhibitors rose from 10.03% of total NSAIDs prescribed by specialty physicians to 29.79%, and from 1.52% to 10.78% of NSAIDs prescribed by primary care physicians (98.23% of NSAIDs and 94.61% of COX-2 inhibitors were prescribed by primary care physicians). For specialty physicians, rofecoxib and celecoxib were third and fifth most frequently prescribed NSAIDs but first and second in cost, respectively; for primary-care physicians they were ninth and twelfth most frequently prescribed NSAIDs and first and fourth in cost.

The cause of the rapid widespread acceptance of Celebrex and Vioxx by physicians was the publication of two large trials, the Celecoxib Long-term Arthritis Safety Study ^[5] CLASS study in JAMA, and the Vioxx Gastrointestinal Outcomes Research^[6] VIGOR study in the New England Journal of Medicine. Both publications concluded that COX-2 specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial comparing Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis or rheumatoid arthritis for six months, Celebrex was significantly associated with fewer upper gastrointestinal complications (0.44% vs. 1.27%, P=0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin for cardiovascular prophylaxis. In the VIGOR trial testing Vioxx 50 mg/day versus naproxen for rheumatoid arthritis, Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events (perforations, obstructions and bleeding) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health.

Comparative studies

In a metaanalysis of eight osteoarthritis studies, the incidence of withdrawal because of adverse gastrointestinal events was 3.5% for Vioxx, compared to 4.8% for ibuprofen, diclofenac, or nabumetone (Relafen). Endoscopic studies of patients receiving Celebrex 50–400 mg twice daily for 12–24 weeks found rates of upper gastrointestinal complications similar to placebo and significantly lower than naproxen 500 mg twice daily and ibuprofen 800 mg three times daily, but not statistically significantly different from patients receiving diclofenac 75 mg twice daily.11 The analysis found that Vioxx provided significant gastrointestinal benefits in patients both at high risk and at low risk of developing gastrointestinal problems; patients at low risk still had 88% fewer gastrointestinal problems with Vioxx.

The results of the CLASS study were confirmed by the Successive Celecoxib Efficacy and Safety Studies (SUCCESS) study, which examined the effectiveness and safety of celecoxib 200 mg and 400 mg daily and how well it was tolerated by patients in terms of adverse effects, compared with the most common NSAID regimens in the countries studied (diclofenac 100 mg daily and naproxen 1000 mg daily). SUCCESS showed that celecoxib was as effective as the conventional NSAIDs in controlling the pain of arthritis, and caused fewer gastrointestinal ulcers or ulcer complications (such as perforations or bleeding) and fewer upper gastrointestinal adverse effects, e.g. 29% less chance of having nausea and 22% less chance of abdominal pain. In addition, hospitalization rates for upper gastrointestinal problems were 2 to 4 times lower with celecoxib, and because there were fewer adverse effects, there was 23% less chance of a celecoxib patient stopping treatment. The study also found that there was no real advantage to taking a bigger dose of celecoxib: the 200 mg dose was found to be just as effective as the 400 mg dose.

The VIGOR study was followed by the Assessment of Difference between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness (ADVANTAGE) study, which showed that 9.1% of people taking Vioxx received a gastro-protective medicine compared with 11.2% of people taking naproxen, a reduction of 19%. In addition, after 3 months, 5.9% of people stopped taking Vioxx compared with 8.1% who stopped taking naproxen, a reduction of 27%. ADVANTAGE was the first study comparing the gastrointestinal tolerability of Vioxx and naproxen in a group that included patients taking low-dose aspirin for cardiovascular reasons. This was followed by the Experience with Vioxx in Arthritis (EVA) survey of 5,986 Belgian physicians and 74,192 people with osteoarthritis, which found that, after 12.5 or 25 mg of Vioxx once daily for 30 days, 80% of the patients wished to continue treatment with Vioxx and more than 80% of doctors said they would continue prescribing Vioxx. The preference to continue taking Vioxx was especially strong in people previously treated with older NSAIDs.

In a six week long study comparing Vioxx 25 mg once daily, Vioxx 12.5 mg once daily, Celebrex 200 mg once daily, and paracetamol/acetaminophen 1,000 mg four times daily for osteoarthritis of the knee, higher dose Vioxx was found to be superior to the other three treatments for reduction of nocturnal pain, and superior to Celebrex and acetaminophen/paracetamol for reduction of resting pain. At six weeks, 60% of high dose Vioxx patients reported a good or excellent response, compared to 46% of Celebrex patients and 39% of paracetamol patients. Low dose Vioxx was not found to be statistically significant from Celebrex at this dose. Similar results were found for early response to therapy.

However, when the Food and Drug Administration (FDA) later presented more complete data from the CLASS and VIGOR trials on its web site, the results were less certain. The CLASS trial was revealed to also have twelve and fifteen month time points which had not been discussed in the JAMA publication; in this segment of the trial, the number of ulcer-related complications for Celebrex caught up to the control NSAID group. Similarly, the complete VIGOR study data revealed that in fact, when all adverse events, not just gastrointestinal, were tabulated, the patients receiving VIOXX had suffered (barely) significantly higher incidence of adverse events overall than the control NSAID group. In particular, the risk of serious cardiovascular thrombotic events, e.g. myocardial infarction, was 1.7% in the VIOXX patients versus 0.7% in the control group, and there were significantly more withdrawals in the Vioxx group for causes including hypertension, edema, hepatotoxicity, heart failure, or pathological laboratory findings. The mean increases in systolic and diastolic blood pressure in the Vioxx group were 4.6 mmHg and 1.7 mmHg respectively, compared to 1.0 and 0.1 mmHg in the control NSAID group. An estimated 43,000,000 Americans, nearly one out of six, suffers from arthritis. However, 42% (18 million) of these also suffer from hypertension. Therefore, the promise of better patient outcomes and lowered medical costs from use of COX-2 inhibitors may not be as great as previously hoped. Questions remain regarding the relative safety and cost effectiveness of this new class. While endoscopic evidence of gastrointestinal damage is frequently seen in studies of nonspecific NSAIDs, the actual incidence of clinically evident symptoms and patient discomfort is much lower; furthermore, in cases of short-term therapy, any such damage generally reverses itself quickly after termination of the drug.

Combination drugs

A model comparing the theoretical relative frequency of gastrointestinal adverse effects and cost effectiveness of celecoxib, nonspecific NSAIDs alone, NSAIDs plus a proton pump inhibitor, NSAIDs plus an H₂ receptor antagonist, NSAIDs plus misoprostol, and diclofenac/misoprostol, found the lowest probability of adverse gastrointestinal events for celecoxib, followed by NSAIDs plus a proton pump inhibitor, NSAIDs plus an H₂ receptor antagonist, NSAID plus misoprostol, diclofenac/misoprostol, and NSAID alone. In total cost, including drug plus treatment of any gastrointestinal effects, the lowest cost treatment was celecoxib, followed by NSAIDs alone and diclofenac/misoprostol, with the other NSAID plus gastrointestinal protection regimens being much more costly. Similarly, a model of cost effectiveness of rofecoxib and celecoxib compared to high-dose acetaminophen or ibuprofen, with and without misoprostol, in patients with osteoarthritis of the knee found that acetaminophen had the lowest cost for average patients. For those not responding to paracetamol, ibuprofen was the most cost effective treatment by a large margin, but for those who did not respond to acetaminophen and had a high risk of gastrointestinal damage, rofecoxib was the most cost effective treatment.

Risks and adverse effects

This cardiovascular risk of COX-2 specific inhibitors is not surprising since prostaglandins are involved in regulation of blood pressure by the kidneys. Therefore, cardiovascular effects of NSAIDs prescribed for arthritis pain and inflammation need to be considered when choosing the appropriate medication for each patient. A French study of osteoarthritis patients over 65 years of age determined that, compared to Celebrex (200 mg once daily), patients taking Vioxx (25 mg once daily) suffered a two-fold increase in clinically significant edema and 60% more frequent increases in systolic blood pressure greater than 20 mmHg, as early as the second week of treatment. This has significant implications, since it has been estimated that every 2 mmHg increase in blood pressure raises the risk of stroke by two thirds and the risk of myocardial infarction by one third, suggesting that Celebrex may be a better choice for hypertensive patients or those at risk for edema. In addition, COX-2 inhibitors lack some of the platelet inhibiting properties of aspirin and other nonspecific NSAIDs and may, directly or indirectly, lead to increased risk of thrombosis, particularly in high risk patients where low dose aspirin therapy is warranted. On the other hand, this property makes them a better choice for perisurgical pain management, where inhibition of blood clotting would be problematic. Also, long-term use of COX-2 inhibitors is not safe, and for patients with chronic arthritis, the choices for prescription drugs for long-term treatment, is limited.

There are other differences between Celebrex and Vioxx that influence prescribing practices. Patients with known sensitivity to sulfa drugs are likely to be sensitive to Celebrex as well, due to similarity in structure. Vioxx has a more rapid onset and is approved for acute pain as well as osteoarthritis, while Celebrex is approved for rheumatoid arthritis as well as osteoarthritis.

Considerations for prescription

A key assumption made in early COX-2 cost-effectiveness studies was lower cost due to a reduction in coprescription of agents used to protect the gastrointestinal tract from traditional NSAIDs. However, if gastroprotective agents continue to be coprescribed along with COX-2 inhibitors, there would seem to be no advantage to the use of these higher cost NSAIDs. Similarly, in patients who take aspirin for cardiovascular benefit, with its attendant gastrointestinal irritation, prescription of COX-2 inhibitors to avoid gastrointestinal irritation would seem to offer no advantage. This was confirmed by the CLASS study, which found significantly lower incidence of upper gastrointestinal complications alone and combined with symptomatic ulcers in patients taking Celebrex 400 mg twice daily, compared to ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily; but this freedom from gastrointestinal complications was lost in patients taking concurrent low dose aspirin.

Future of COX-2 inhibitors

Neuroblastomas

Recent studies have shown that small tumors of the sympathetic nervous system (neuroblastoma) have abnormal levels of COX-2 expressed.^[7] These studies report that overexpression of the COX-2 enzyme has an adverse effect on the tumor suppressor, p53. p53 is an apoptosis transcription factor normally found in the cytosol. When cellular DNA is damaged beyond repair, p53 is transported to the nucleus where it promotes p53 mediated apoptosis.^[8] Two of the metabolites of COX-2, prostaglandin A2 (PGA2) and A1 (PGA1), when present in high quantities bind to p53 in the cytosol and inhibit its ability to cross into the nucleus. This essentially sequesters p53 in the cytosol and prevents apoptosis.^[8] coxibs such as CELEBREX (celecoxib), by selectively inhibiting the overexpressed COX-2, allow p53 to work properly. Functional p53 allows DNA damaged neuroblastoma cells to commit suicide through apoptosis, halting tumor growth. COX-2 up-regulation has also been linked to the phosphorylation and activation of the E3 ubiquitin ligase HDM2, a protein that mediates p53 ligation and tagged destruction, through ubiquitination.^[8] The mechanism for this neuroblastoma HDM2 hyperactivity is unknown. Studies have shown that COX-2 inhibitors block the phosphorylation of HDM2 preventing its activation. In vitro, the use of COX-2 inhibitors such as CELEBREX (celecoxib) lowers the level of active HDM2 found in neuroblastoma cells. The exact process of how COX-2 inhibitors block HDM2 phosphorylation is unknown, but this mediated reduction in active HDM2 concentration level restores the cellular p53 levels. After treatment with CELEBREX (celecoxib), the restored p53 function allows DNA damaged neuroblastoma cells to commit suicide through apoptosis reducing the size of growth of the tumor.^[8]

Cancer

COX-2 appears to be related to cancers and abnormal growths in the intestinal tract. COX inhibitors have been shown to reduce the occurrence of cancers and pre-cancerous growths. The National Cancer Institute has done some studies on COX-2 and Cancer.^[9] And the FDA has approved Celebrex for treatment of familial adenomatous polyposis (FAP) [1]. COX-2 inhibitors are currently being studied breast cancer^[10] and appear to be beneficial.^[11]

Other targets

The inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of the selective COX-2 inhibitor celecoxib, and quite likely also for its ability to prevent the development of cancerous growth^{[citation needed]}. However, with regards to this drug’s promise for the therapy of advanced cancers, it is unclear whether the inhibition of COX-2 plays a dominant role, and this has become a controversial and intensely researched issue. In recent years, several additional intracellular components (besides COX-2) were discovered that appear to be important for mediating the anticancer effects of celecoxib in the absence of COX-2.^[12] Moreover, a recent study with various malignant tumor cells showed that celecoxib could inhibit the growth of these cells, even though some of these cancer cells didn’t even contain COX-2.^[13]

Additional support for the idea that other targets besides COX-2 are important for celecoxib’s anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures.^[14] Some of these analogs retained COX-2 inhibitory activity, whereas many others didn’t. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, it turned out that the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing that inhibition of COX-2 was not required for the anticancer effects.^[14][15] One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually turned out to display stronger anticancer activity than celecoxib itself ^[16] and this anticancer effect could also be verified in highly drug-resistant tumor cells ^[17] and in various animal tumor models.^[18][19]

See also

• Cyclooxygenase

References

1. ^ Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (July 1991). "TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue". J. Biol. Chem. 266 (20): 12866–72. PMID 1712772. 
2. ^ Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL (April 1991). "Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing". Proceedings of the National Academy of Sciences of the United States of America 88 (7): 2692–6. doi:10.1073/pnas.88.7.2692. PMC 51304. PMID 1849272. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=51304. 
3. ^ Yajnik J (2006-10-27). "University sues Pfizer over COX-2 research". The Scientist. http://www.the-scientist.com/news/display/25408/. Retrieved 2010-11-11. 
4. ^ Tom Harvey (2010-09-21). "BYU spices up Celebrex lawsuit against Pfizer". The Salt Lake Tribune. http://www.sltrib.com/sltrib/money/49883490-79/byu-pfizer-simmons-celebrex.html.csp. Retrieved 2011-02-28. 
5. ^ Silverstein FE, Faich G, Goldstein JL, et al. (September 2000). "Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study". JAMA 284 (10): 1247–55. doi:10.1001/jama.284.10.1247. PMID 10979111. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=10979111. 
6. ^ Bombardier C, Laine L, Reicin A, et al. (November 2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group". N. Engl. J. Med. 343 (21): 1520–8, 2 p following 1528. doi:10.1056/NEJM200011233432103. PMID 11087881. 
7. ^ Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjörnsson B, Kogner P (October 2004). "Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo". Cancer Res. 64 (20): 7210–5. doi:10.1158/0008-5472.CAN-04-1795. PMID 15492235. 
8. ^ ^{a b c d} Lau L, Hansford LM, Cheng LS, Hang M, Baruchel S, Kaplan DR, Irwin MS (March 2007). "Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma". Oncogene 26 (13): 1920–31. doi:10.1038/sj.onc.1209981. PMID 16983334. 
9. ^ "COX-2 Inhibitors and Cancer". Fact Sheet. United States National Cancer Institute. http://www.cancer.gov/cancertopics/factsheet/APCtrialCOX2QandA. 
10. ^ Chow LW, Loo WT, Toi M (October 2005). "Current directions for COX-2 inhibition in breast cancer". Biomed. Pharmacother. 59 Suppl 2: S281–4. doi:10.1016/S0753-3322(05)80046-0. PMID 16507393. http://linkinghub.elsevier.com/retrieve/pii/S0753-3322(05)80046-0. 
11. ^ Farooqui M, Li Y, Rogers T, et al. (December 2007). "COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia". Br. J. Cancer 97 (11): 1523–31. doi:10.1038/sj.bjc.6604057. PMC 2360252. PMID 17971769. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2360252. 
12. ^ Schönthal AH (December 2007). "Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy". Br. J. Cancer 97 (11): 1465–8. doi:10.1038/sj.bjc.6604049. PMC 2360267. PMID 17955049. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2360267. 
13. ^ Chuang HC, Kardosh A, Gaffney KJ, Petasis NA, Schönthal AH (2008). "COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro". Mol. Cancer 7: 38. doi:10.1186/1476-4598-7-38. PMC 2396175. PMID 18485224. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2396175. 
14. ^ ^{a b} Zhu J, Song X, Lin HP, et al. (December 2002). "Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents". J. Natl. Cancer Inst. 94 (23): 1745–57. PMID 12464646. http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12464646. 
15. ^ Schönthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA (February 2008). "Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs". Expert Opin Investig Drugs 17 (2): 197–208. doi:10.1517/13543784.17.2.197. PMID 18230053. 
16. ^ Schönthal AH (2006). "Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy". Neurosurg Focus 20 (4): E21. doi:10.3171/foc.2006.20.4.14. PMID 16709027. 
17. ^ Kardosh A. et al. (2005). "Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib". Blood 106 (13): 4330–8. doi:10.1182/blood-2005-07-2819. PMID 16123214. 
18. ^ Pyrko P. et al. (2007). "Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib". Mol. Cancer Ther. 6 (4): 1262–75. doi:10.1158/1535-7163.MCT-06-0629. PMID 17431104. 
19. ^ Kardosh A. et al. (2005). "Dimethyl-celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-inhibitory function, potently mimics the anti-tumor effects of celecoxib on Burkitt's lymphoma in vitro and in vivo". Cancer Biol. Ther. 4 (5): 571–582. doi:10.4161/cbt.4.5.1699. PMID 15846081. 

Further reading

• Green GA (2001). "Understanding NSAIDs: from aspirin to COX-2". Clin Cornerstone 3 (5): 50–60. doi:10.1016/S1098-3597(01)90069-9. PMID 11464731. 
• Malhotra S, Shafiq N, Pandhi P (2004). "COX-2 Inhibitors: A CLASS Act or Just VIGORously Promoted". MedGenMed 6 (1): 6. PMC 1140734. PMID 15208519. http://www.medscape.com/viewarticle/47342. 
• Montero Fernández MJ, Rodríguez Alcalá FJ, Valles Fernández N, López de Castro F, Esteban Tudela M, Cordero García B (October 2002). "[At what care level are cyclo-oxygenase-2 inhibitors prescribed?"] (in Spanish; Castilian). Aten Primaria 30 (6): 363–7. PMID 12396942. http://db.doyma.es/cgi-bin/wdbcgi.exe/doyma/mrevista.pubmed_full?inctrl=05ZI0105&rev=27&vol=30&num=6&pag=363. 
• "You and A: Arthritis drugs. Pain and confusion"; Francesca Lunzer Kritz; Washington Post; Sept. 4, 2001; HE01.
• "Vioxx (rofecoxib) reduces night-time osteoarthritis pain better than celecoxib or acetaminophen"; European League Against Rheumatism (EULAR) conference proceedings.
• "Will the promise of the COX-II selective NSAIDs come to fruition?"; Drug Ther Perspect 17(11); 6-10, 2001.
• Chancellor JV, Hunsche E, de Cruz E, Sarasin FP (2001). "Economic evaluation of celecoxib, a new cyclo-oxygenase 2 specific inhibitor, in Switzerland". Pharmacoeconomics 19 Suppl 1: 59–75. doi:10.2165/00019053-200119001-00005. PMID 11280106. 
• Kamath CC, Kremers HM, Vanness DJ, O'Fallon WM, Cabanela RL, Gabriel SE (2003). "The cost-effectiveness of acetaminophen, NSAIDs, and selective COX-2 inhibitors in the treatment of symptomatic knee osteoarthritis". Value Health 6 (2): 144–57. doi:10.1046/j.1524-4733.2003.00215.x. PMID 12641865. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1098-3015&date=2003&volume=6&issue=2&spage=144. 
• "Osteoarthritis drug Celebrex (celecoxib) less likely to cause increased blood pressure than Vioxx (rofecoxib)"; European League Against Rheumatism (EULAR) conference proceedings.
• Johnsen JI, Lindskog M, Ponthan F, et al. (October 2004). "Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo". Cancer Res. 64 (20): 7210–5. doi:10.1158/0008-5472.CAN-04-1795. PMID 15492235. 
• Dai C, Stafford RS, Alexander GC. National Trends in Cox-2 inhibitor use since market release: non-selective diffusion of a selectively cost-effective innovation Archives of Internal Medicine. 2005; 165: 171-177.
• Editorial: Solomon DH, Avorn J. Coxibs, science, and the public trust Archives of Internal Medicine. 2005;165:158-160