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Discover magazine cover for June 2001
June 2001

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[Archived as a public service to help patients understand NSAIDs and COX-2 inhibitors.]

Does Aspirin Help Prevent Cancer?
Perhaps, but the side effects could get you too

By Karen Wright

Will cancer prevention ever come in the form of a pill? Maybe it already does. Evidence is mounting that ordinary, over-the-counter painkillers millions of Americans use regularly for headaches, muscle soreness, and arthritis might also lower their chances of developing certain types of cancer. Doctors call the class of compounds nonsteroidal anti-inflammatory drugs, or NSAIDs, but you might know them by more familiar names: aspirin, ibuprofen, and naproxen, to list a few.

Studies conducted during the past decade suggest that aspirin and its relatives can slow the growth of many kinds of tumors, most notably those that cause colorectal cancer, the third most common cause of cancer deaths in the United States. In some cases, NSAIDs seemed to cut the incidence of colorectal cancer by as much as half. The National Cancer Institute is currently sponsoring clinical trials that will produce more conclusive results. But the new research has also heightened long-standing concerns about the dangers associated with these drugs.

"If you're thinking in terms of preventing cancer, rather than treating it, you need a very, very safe approach," says gastroenterologist Andrew Dannenberg, who directs the cancer prevention program at New York Presbyterian Hospital-Cornell and conducts research at Cornell University. Despite their ready availability, he says, "NSAIDs are not really safe compounds."

Cancer researchers have suspected since the 1970s that NSAIDs might retard the growth of colorectal tumors. The biochemical basis for this action is simple. Colorectal cancer is often preceded by chronic inflammation of the lining of the gut and an increase in the natural substances, called prostaglandins, that cause it. NSAIDs can combat inflammation by inhibiting prostaglandin synthesis. So it has long been thought that they might guard against cancer as well. In the 1980s, studies showed reduced rates of colorectal cancer in arthritis sufferers who were treating their pain with daily doses of NSAIDs. Observational evidence for the drugs' preventive effects continued to pile up in the 1990s.

But aspirin and its cohorts come with some nasty side effects that have kept doctors from taking them seriously as anticancer agents. Because one of the enzymes they inhibit helps maintain the lining of the gut, NSAIDs can cause bleeding ulcers and other injuries of the digestive tract. These NSAID-related traumas result in about 100,000 hospitalizations and almost 17,000 deaths a year in the United States. Physicians can't predict which patients will suffer these adverse reactions, so the idea of advocating long-term use of the drugs in healthy people has never seemed sound.

Of course, the toxicity of NSAIDs limits their use in controlling chronic pain and treating arthritis as well. Lured by those multibillion-dollar markets, pharmaceutical companies began about a decade ago to develop a safer NSAID. The compounds work by targeting enzymes called cyclooxygenases that help build prostaglandins. One of the enzymes, called COX-1, helps maintain the gut lining and a host of other normal tissues as well. Another, COX-2, seems to be less involved in healthy body functions and most responsive in inflammatory reactions. If they could confine the activity of the anti-inflammatories to damping down COX-2, drug developers reasoned, they might eliminate some of the gastrointestinal side effects. Thus the new NSAIDs are called selective COX-2 inhibitors; two examples on the U.S. market today are celecoxib and rofecoxib, prescription drugs that go by the brand names Celebrex and Vioxx.

Cancer researchers began testing the new compounds in animals as soon as they were synthesized. At the same time studies began documenting a connection between the COX-2 enzyme and cancer. Researchers reported abnormally high levels of COX-2 in tumors and premalignant growths of the esophagus, stomach, breast, prostate, lung, bladder, pancreas, skin, cervix, head, and neck as well as the colon and rectum. Once again, the link emerged most strongly in colorectal cancer. In the mid-1990s, for example, scientists knocked out the gene for COX-2 in a strain of mice genetically predisposed to cancer of the gut. Without the enzyme, these mice had an 86-percent reduction in the number of intestinal polyps, the precursors to colorectal cancer. Treatment with a selective COX-2 inhibitor had similar results in the high-risk mice. And celecoxib was shown to cause nearly complete suppression of chemically induced colon cancer in rats.

Prompted by such reports, researchers at M.D. Anderson Cancer Center in Houston recently undertook the first clinical trials of selective COX-2 inhibitors in people. Their subjects had a rare genetic condition that results in an unusually high risk of colorectal cancer. In six months of daily use, celecoxib reduced the number of polyps in these patients by 28 percent. The significance of the reductions for cancer rates and deaths over the long haul still needs to be demonstrated. But the results bode well for preventing common colorectal cancer, which probably shares the same vulnerability to COX-2 inhibition, says Dannenberg.

"COX-2 is a gene that gets turned on early in the disease," he says. While that means NSAIDs may not have much effect on full-blown tumors, they could halt the decades-long progression toward malignancy. "I think of this as treatment for carcinogenesis," says Dannenberg, "not cancer."

Other investigators are not so sanguine. Some question the emphasis on the COX-2 pathway of prevention, arguing that NSAIDs may work by other means that shouldn't be overlooked. In laboratory studies, for example, NSAIDs that don't act on cyclooxygenases are still able to slow or reverse cancer-related changes in cells. In human trials, however, "we haven't found them to be as effective," says Ernest Hawk of the National Cancer Institute's division of prevention.

Other critics wonder whether the next-generation NSAIDs are any safer than the last generation. "The benefits of COX-2 inhibitors as far as reducing GI [gastrointestinal] toxicity appear to have been grossly exaggerated and oversold," claimed experts for the Public Citizen Health Research Group in a statement before a Food and Drug Administration committee in February. The same group warned that some COX-2 specific drugs might damage the heart, citing evidence from animal studies and the opinion of one of the administration's own reviewers. The new drugs also come with price tags that may be hard to justify. At $1 to $2 a dose, COX-2 selective NSAIDs are a lot more expensive than their predecessors. That's why aspirin and other traditional NSAIDs are now being tested alongside the newcomers in about a dozen government-sponsored clinical trials.

"Right now it's premature to recommend aspirin or any other NSAID for cancer prevention," says Hawk. "We don't know which one is most effective, or at what dose, and we don't know enough about the side effects." Answers to these questions should be available in a few years.

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