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Andrew J. Dannenberg, MD
Henry R. Erle, MD-Roberts Family Professor of Medicine
Weill Medical College of Cornell University
Co-Director
Cancer Prevention Program
Columbia Weill Cornell Cancer Centers
NewYork-Presbyterian Hospital
New York, New York

The past decade has borne witness to a series of studies suggesting that the enzyme cyclooxygenase (COX) represents a bona fide therapeutic target for cancer prevention and possibly treatment. Epidemiological studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of several malignancies, including colorectal cancer. These drugs inhibit the activity of COX enzymes; this ability suggests that prostaglandins, the products of COX metabolism, contribute to cancer development.

The two isoforms of COX, COX-1 and COX-2, differ in various respects. COX-1 is constitutively expressed in most tissues and mediates the production of prostaglandins that control normal physiological functions, including maintenance of the gastric mucosa and renal blood flow.(1) In contrast, COX-2 is absent in most normal tissues. However, oncogenes, growth factors, and tumor promoters induce COX-2, resulting in enhanced expression in premalignant tissues and in malignant tumors.(1,2) Several lines of evidence have linked COX-2 to carcinogenesis. The most specific data that support a cause-and-effect connection between COX-2 and tumorigenesis come from genetic studies. Mice engineered to overexpress human COX-2 in mammary glands develop mammary cancer.(3) Conversely, knocking out the COX-2 gene protected against the formation of both intestinal and skin tumors.(4,5) In addition to the genetic evidence, preclinical pharmacological studies indicate that COX-2 is a pharmacological target. Treatment with selective inhibitors of COX-2 reduces the formation, growth and metastases of numerous tumor types in experimental animals.(2,6-9) Several different mechanisms have been identified that can explain the anti-tumor activity of selective COX-2 inhibitors. These agents inhibit angiogenesis, induce apoptosis, suppress cell proliferation and enhance immune surveillance.(2,10,11)

Safety is a critical consideration for any medication that will be used for extended periods of time in an effort to prevent cancer. Importantly, selective COX-2 inhibitors have been used extensively to treat patients with arthritis and have an excellent safety profile.(12) The first human trial to evaluate the anti-cancer properties of a selective COX-2 inhibitor is complete. This study was carried out in familial adenomatous polyposis (FAP) patients because of the strength of preclinical data and prior evidence that sulindac, which inhibits COX-1 and COX-2, reduced the number of colorectal polyps in these patients. Treatment with celecoxib 400 mg twice daily for 6 months reduced the number of colorectal polyps by 28% (P = 0.003).(13) A reduction in duodenal polyposis was also observed. Based on these results, the FDA approved celecoxib as adjunctive therapy for the management of colorectal polyps in FAP patients. Similarities in the biology of FAP and sporadic colorectal cancer mean that therapeutic strategies that are effective in FAP might also be applicable in patients at risk for sporadic colorectal adenomas. Because colorectal adenomas are the precursors of the majority of colorectal cancers, treatments that decrease the formation of premalignant adenomas may protect against the development of colorectal cancer. Several large clinical trials are under way to assess the efficacy of selective COX-2 inhibitors (celecoxib and rofecoxib) in preventing sporadic colorectal adenomas.

As mentioned above, selective COX-2 inhibitors protect against the formation of multiple tumor types in experimental animals. Ongoing phase II trials are building on these preclinical studies by evaluating the potential utility of selective COX-2 inhibitors in a variety of target organs. At risk cohorts being studied include patients with premalignant oral lesions, Barrett's dysplasia, bronchial metaplasia, basal cell nevi and actinic keratoses.(2) Given the frequent need for surgical intervention in conditions such as Barrett's dysplasia and oral leukoplakia, developing a pharmacological approach to cause either disease stabilization or regression would represent a significant clinical advance. Another study is evaluating whether a selective COX-2 inhibitor prevents or delays the recurrence of bladder cancer in patients with a history of superficial bladder cancer.

Drugs that are useful in preventing cancer may also be effective in treating cancer. Although many cancer treatment studies are under way, it is too soon to know whether selective COX-2 inhibitors will be useful. Selective COX-2 inhibitors are being evaluated in conjunction with chemotherapy and radiotherapy in patients with cancers of the colon, lung, breast, esophagus, pancreas, liver and cervix.(2) In a recently completed phase II neoadjuvant trial involving 29 patients with non-small-cell lung cancer (NSCLC), we evaluated whether the addition of celecoxib enhanced the anti-tumor activity of paclitaxel and carboplatin.(14) The overall clinical response was higher than predicted from historical data suggesting that the addition of a selective COX-2 inhibitor might enhance the response to preoperative paclitaxel and carboplatin. A confirmatory placebo-controlled trial is being initiated. Other investigators are conducting phase II trials of celecoxib and docetaxel in NSCLC.

Given the strength of the preclinical evidence, numerous trials are evaluating selective COX-2 inhibitors in the treatment of colorectal cancer. In a retrospective study of patients with metastatic colorectal cancer, the addition of celecoxib to capecitabine delayed tumor progression and improved overall survival. This finding provided a rationale for a phase II trial that will evaluate this combination regimen. Another study will evaluate whether rofecoxib can prevent or delay the recurrence of colorectal cancer following potentially curative surgery.

In addition to determining whether selective COX-2 inhibitors enhance the anti-tumor activity of chemotherapy, other approaches are being evaluated. For example, celecoxib is being evaluated in conjunction with chemoradiation in patients with locally advanced cervical cancer. Another study is evaluating a selective COX-2 inhibitor with limited field radiation in patients with locally advanced NSCLC. In yet another phase II study, a selective COX-2 inhibitor is being given before surgery in patients with prostate cancer with the goal of better defining the effects of the drug on tumor biology.

The role of selective COX-2 inhibitors continues to evolve. While these agents are widely used to treat arthritis and pain, inhibiting COX-2 may also prove to be an important form of targeted therapy to prevent or treat human malignancies. Given the strength of the preclinical findings and the promise of the proof-of-principle clinical trial in FAP patients, the results of ongoing clinical trials are anxiously awaited.

References

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2. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci. 2003;24:96-102.
3. Liu CH, Chang SH, Narko K, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Bio. Chem. 2001;276:18563-18569.
4. Tiano HF, Loftin CD, Akunda J, et al. Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res. 2003;62:3395-3401.
5. Chulada PC, Thompson MB, Mahler JF, et al. Genetic disruption of Ptgs-1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res. 2000;60:4705-4708.
6. Kawamori T, Rao CV, Seibert K, et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res. 1998;58:409-412.
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9. Howe LR, Subbaramaiah K, Patel J, et al. Celecoxib, a selective cyclooxygenase-2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res. 2003;62:5405-5407.
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11. Williams CS, Tsujii M, Reese J, et al. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest. 2000;105:1589-1594.
12. FitzGerald GA, Patrono C. The COXIBS, selective inhibitors of cyclooxygenase-2. New Engl J Med. 2001;345:433-442.
13. Steinbach G, Lynch PM, Phillips RKS, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Eng. J Med. 2000;342:1946-1952.
14. Altorki NK, Keresztes RS. Port JL, et al. Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol. 2003;21:2645-2650.