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The Anticancer Properties of Selective COX-2 Inhibitors
New Directions for Prevention and Treatment
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 the 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, which suggests that prostaglandins, the products of COX metabolism, contribute to cancer development.
There are two forms of COX--COX-1 and COX-2-and they differ in various respects. COX-1 can be found, or expressed, in most tissues in the body and mediates the production of prostaglandins that control normal physiological functions, including the maintenance of the gastric mucosa and renal blood flow. In contrast, COX-2 is absent in most normal tissues. However, a number of substances found in the body, such as oncogenes, growth factors, and tumor promoters that are linked to cancer development, can induce COX-2, which results in increased COX-2 levels in both premalignant tissues and in malignant tumors.
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 the development of tumors come from genetic studies in laboratory animals. Mice engineered to overexpress human COX-2 in mammary glands have been shown to develop mammary cancer. Conversely, knocking out the COX-2 gene has been demonstrated to protect laboratory animals against the formation of both intestinal and skin tumors. In addition to this genetic evidence, preclinical pharmacological studies indicate that COX-2 is a pharmacological target for cancer prevention. Treatment with selective inhibitors of COX-2 reduces the formation, growth, and metastases of numerous tumor types in experimental animals. Several different mechanisms have been identified that can explain the antitumor activity of selective COX-2 inhibitors. These agents inhibit angiogenesis, or the development of blood vessels to feed tumor growth; induce apoptosis, or programmed cell death; suppress cell proliferation; and enhance immune surveillance.
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 been shown to have an excellent safety profile. The first human trial to evaluate the anticancer properties of a selective COX-2 inhibitor is complete. This study was carried out in patients with familial adenomatous polyposis (FAP)--a condition that increases their risk of developing colorectal cancer--because of the strength of preclinical data as well as clinical data that showed 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%. A reduction in duodenal polyposis was also seen. Based on these results, the Food and Drug Administration (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 patients also might be applicable in patients at risk for sporadic colorectal adenomas, which are the precursors of the majority of colorectal cancers. Thus, treatments that decrease the formation of premalignant adenomas might 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.
Based on the evidence of preclinical studies in laboratory animals that selective COX-2 inhibitors protect against the formation of many different types of tumors, ongoing phase II trials are evaluating if these agents may have the same effect in humans. Investigators are studying the potential of selective COX-2 inhibitors in patients who have an increased risk of developing various malignancies, including those with premalignant oral leukoplakia (oral cancer), Barrett's dysplasia (esophageal cancer), bronchial metaplasia (lung cancer), basal cell nevi and actinic keratoses (skin cancer). 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. Furthermore, 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 also may be effective in treating cancer. Although many cancer treatment studies are underway, 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 radiation in patients with cancers of the colon, lung, breast, esophagus, pancreas, liver, and cervix. In a recently completed phase II study of 29 patients with nonsmall-cell lung cancer (NSCLC), researchers evaluated whether the addition of celecoxib enhanced the antitumor activity of paclitaxel and carboplatin, two chemotherapy agents commonly used to treat this malignancy. Patients were treated with these drugs prior to their surgery for NSCLC. The overall clinical response was higher than what was expected, based on the results of other studies of these two chemotherapy agents. This suggests that the addition of a selective COX-2 inhibitor might enhance the response to preoperative paclitaxel and carboplatin. A confirmatory placebo-controlled trial will start soon. Other investigators are conducting phase II trials of celecoxib and docetaxel, a chemotherapy drug similar to paclitaxel, in patients with 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 the chemotherapy agent capecitabine delayed tumor progression and improved overall survival. This finding has 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 antitumor activity of chemotherapy, other approaches are being evaluated. For example, celecoxib is being evaluated in conjunction with chemotherapy plus radiation 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.
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