By Cynthia Washam

For more than 100 years‚ people have used aspirin for pain relief. But not until the past 30 years has it been clear why aspirin works—and the discovery has led to some amazing connections to cancer that range from prevention to treatment.

Aspirin’s journey from pain reliever to cancer killer started some three decades ago when 1982 Nobel Prize winner Sir John Vane‚ PhD‚ discovered that aspirin and other pain relievers like Advil® and Motrin® (ibuprofen) were stopping the formation of prostaglandins‚ the fatty substances similar to hormones that lead to inflammation (pain‚ swelling‚ and redness of injured tissues).

The formation of prostaglandins is due to an enzyme they called COX‚ short for cyclooxygenase. Twenty years ago most scientists believed that the formation of prostaglandins was the work of only one enzyme‚ but Dr. Vane believed that more types of COX enzymes would be discovered.

And he was right. By the mid–1980s several groups across the country were reporting that COX was not just one enzyme‚ but two.

Cancer‚ COX–1‚ and COX–2
COX–1‚ as it was subsequently named‚ is present in most normal tissues‚ especially the stomach and kidneys. The second type of COX enzyme‚ COX–2‚ on the other hand‚ is only present in injured‚ inflamed areas. Aspirin‚ ibuprofen‚ and other arthritis drugs like Clinoril® (sulindac) are called “pan–COX” inhibitors because they work by inhibiting both COX–1 and COX–2.

While effective for pain relief‚ the inhibition of the normal COX–1 enzyme can lead to side effects such as stomach ulcers.

It soon became apparent that the most desirable thing would be to find an inhibitor that only affected COX–2 without inhibiting COX–1.

Enter COX–2 inhibitors Celebrex® (celecoxib) and Vioxx® (rofecoxib)‚ created to relieve symptoms of arthritis and approved for use in arthritis patients in the late ’90s.

The Cancer Connection
Interestingly‚ in addition to being expressed in inflamed tissues‚ COX–2 was also found in high levels in a number of cancers‚ including breast‚ lung‚ and colon cancer‚ suggesting that COX–2 might actually contribute to the development of these tumors.

“COX–2‚ when expressed in a tumor‚ allows new blood vessels to supply the tumor and prevents tumor cells from dying spontaneously‚” says cardiothoracic surgeon Nasser Altorki‚ MD‚ Weill Medical College‚ Cornell University‚ New York.

Studies in animals have shown that COX–2 expression stimulates tumor growth‚ suppresses the immune system from reacting to the tumor‚ and increases the ability of the tumor to spread (metastasize). Not surprisingly‚ the more COX–2 enzyme a tumor produces‚ the worse the prognosis.

Understanding how to use this knowledge in treatment and prevention of cancer could mean a powerful new weapon in the cancer arsenal‚ prompting researchers to explore how inhibiting COX–2 might stop tumor growth and increase the effectiveness of chemotherapy drugs. Now some research suggests that suppressing the enzyme promotes cell suicide and cuts off the blood vessels that nourish tumors. Without a blood supply‚ tumors can’t grow beyond the size of a pea.

“It’s still preliminary‚” Dr. Altorki explains. “But the results have been very encouraging.”

Encouraging Signs
The first indications that pan–COX relievers such as aspirin‚ ibuprofen‚ and sulindac could fight cancer came from personal accounts or patient records.
William Waddell‚ MD‚ department of surgery‚ University of Colorado Health Sciences Center‚ Denver‚ published one of the first reports of colon polyps shrinking or disappearing in patients who were routinely taking pain–relieving drugs. Other studies showed that patients taking one aspirin tablet a day had half the incidence of colon cancer as people who did not.

But the issues of prolonged use of pan–COX inhibitors causing serious consequences limited interest. Over time‚ prolonged use can have serious consequences‚ such as stomach bleeding and ulceration‚ affecting approximately 4% of patients who take the drugs regularly for more than a year. A small percentage of chronic users also develop high blood pressure from the drugs‚ and kidney damage has been seen as well.

However‚ with the recent approval of Celebrex and Vioxx‚ those problems could be overcome because these drugs act by specifically inhibiting COX–2 and COX–2 only; while COX–1‚ required for normal functions in the stomach and kidneys‚ is unaffected.

The ability of COX–2 inhibitors to stop blood vessel growth to the tumor also suggests they could also play another role in cancer treatment by being combined with chemotherapy drugs.

“It appears they can enhance chemotherapy and radiation‚” says radiation oncologist Adam Dicker‚ MD‚ PhD‚ Jefferson Medical College‚ Thomas Jefferson University‚ Philadelphia. “And their toxicity is acceptable.”

At the May 2002 meeting of the American Society of Clinical Oncology (ASCO)‚ Dr. Altorki explained how the arthritis drug Celebrex combined with Taxotere® (docetaxel) resulted in the killing of more than 95% of tumor cells in about a third of his 23 advanced lung cancer patients. Chemotherapy alone produces similar results in only about 6% of lung cancer patients‚ according to Dr. Altorki.

A second study reported at the ASCO meeting by Edward Lin‚ MD‚ M. D. Anderson Cancer Center‚ Houston seems to support this view. Dr. Lin reviewed data on 67 patients with colon cancer who were treated with an oral chemotherapy drug called Xeloda® (capecitabine).

Some of these patients had also been taking Celebrex for arthritis pain. When Dr. Lin examined the effectiveness of chemotherapy in the patients who had been taking Celebrex‚ he found that more achieved tumor shrinkage and they tended to remain in remission for a longer period of time compared to the patients who had not been taking Celebrex. As an added benefit‚ Celebrex seemed to lessen the side effects‚ such as diarrhea‚ associated with Xeloda.

COX–2–Specific Inhibitors: Prevention Too?
Preclinical studies have shown that COX–2–specific inhibitors may prevent as well as treat tumors by stopping proliferation of tumor cells and causing the cells to die in some cases. COX–2 inhibitors also might be able to stimulate the immune system to fight the tumors. All of these activities point to a role for COX–2 inhibitors in both prevention and treatment.

The idea of using COX–2 inhibitors to prevent tumors is strongly supported by its success in familial adenomatous polyposis (FAP) disease‚ a rare genetic disorder that predisposes individuals to the development of precancerous polyps in the colon.

Untreated‚ almost every person with the FAP gene abnormality will eventually develop colon cancer‚ usually by the age of 40. COX–2 inhibitors like Celebrex have shown to be highly effective in preventing the formation of polyps‚ and subsequently reducing the incidence of colon cancer in these patients. A landmark study in patients with FAP who were given Celebrex showed a near 30% reduction in the risk of developing polyps. Based on this study‚ the U.S. Food and Drug Administration (FDA) has approved Celebrex for patients with FAP.

“There have been more than 100 animal studies done on these drugs‚” says Ernest Hawk‚ MD‚ National Cancer Institute (NCI)‚ Bethesda‚ Maryland. “Ninety percent suggest they should reduce colon cancer.”

Not only do they show promise in preventing cancer of the colon‚ but COX–2 inhibitors may also be helpful in the four most prevalent forms of cancer—skin‚ lung‚ prostate‚ and breast.

By far the most prevalent cancer being studied for prevention with COX–2 inhibitors is squamous cell carcinoma of the skin.

“People can die of squamous cell carcinoma‚ but it’s very uncommon‚” says dermatologist Craig Elmets‚ MD‚ University of Alabama‚ Birmingham.
Compared with other types of cancer‚ the risk for squamous cell carcinoma is easy to assess. Patients at greatest risk have actinic keratosis‚ bright red spots on their skin caused by chronic sun exposure.

What Now?
At this time there is too little data to determine who should be taking Celebrex or Vioxx for any reason other than arthritis pain or to prevent polyps if you’re an FAP patient.

But‚ with the number of trials ongoing and the rapidly growing interest of the medical community‚ that’s likely to change‚ and a drug developed for arthritis may help us prevent or even treat certain cancers.