PSA Rising, April 19, 2005. Celebrex and over-the-counter NSAIDs prevent a range of cancers but raise the risk of cardiovascular deaths. This week at the American Association for Cancer Research annual meeting in Anaheim, Calif. researchers presented evidence to show that NSAIDs prevent intestinal, oral, and colon cancers. Cigarette smokers appear to cut in half their risk of dying due to oral cancer if they use non-steroidal anti-inflammatory drugs (NSAIDs).

But these drugs also doubled the smokers' risk of dying from heart attack, stroke, or other heart-related problem. This cancelled out the benefit of avoiding death from oral cancer.

Risk was highest among ibuprofen users, who were nearly three times more likely to die of cardiovascular disease than non-NSAID users. Aspirin was the only NSAID that did not seem to raise the risk, but the numbers of aspirin users in the study were small. Acetaminophen (Tylenol), a non-aspirin pain relief medication, had no effect on cancer risk.

This was the downside of a study by Norwegian and US researchers which found that smokers taking common NSAIDs such as aspirin or ibuprofen had lower risk of oral cancer.

"The use of NSAIDs among smokers protected against oral cancer development," said Jon Sudbø, an oncologist from Norwegian Radium Hospital, Oslo, lead author on the study.

Men who took NSAIDs for six months or longer -- and most had taken them for more than five years -- reduced the risk of developing oral cancer by 50% over smokers who didn't take these autocollimator. Oral cancer proves fatal in about 50% of cases, so the reduction should have led to a lower death rate for the smokers who took NSAIDs.

“The results of a significant reduction in oral cancer risk -- particularly in light to moderate active smokers -- suggest that NSAID use may provide anti-carcinogenetic effect while the smokers are subjecting themselves to tobacco insult,” Sudbø added.

"But then we took a closer look at the data and found that the 50% reduction did not affect the overall mortality rate," Sudbø told a press conference reported by Business Week, Doctor's Guide and other national sources. The NSAID users actually doubled their risk of death from cardiovascular disease.

Sudbø began human studies to investigate the effects of COX-2 inhibitor drugs on oral cancer after finding that people with cancers and pre cancerous abnormalities in the mouth are more likely to have elevated levels of the enzyme Lipooxygenase 2 (COX-2). His team looked to see if COX-2 inhibitors, or coxibs, can prevent these tumors from developing. At that time, Celecoxib (Celebrex) and rofecoxib (Vioxx) were popular coxibs.

Merck pulled Vioxx from the market last fall when a different study, testing whether it could prevent colon cancer, showed a higher heart disease risk. The FDA recently persuaded Pfizer to stop selling Bextra for safety reasons, but Pfizer's Celebrex was allowed to remain bearing a "Black Box" warning label. According to Canadian Press, some researchers from the new study in Norway have been Pfizer consultants.

Sudbø said that because the patients in the study reported this week "took many different types of NSAIDs," no one drug stood out as the culprit. He said NSAIDs which had the effect of preventing oral cancer in smokers included aspirin, ibuprofen, naproxen, indomethacine, piroxicame, and ketoprofene.

Several other studies presented at the AACR, Anaheim, Calif. meeting focused on NSAIDs and cancer. Researchers from the Albert Einstein Cancer Center reported that in mouse models of intestinal cancer, use of the anti-inflammatory drug sulindac eliminated all of the cancer-causing risks produced by a high-fat Western-style diet even when several genetic brakes to cancer formation were missing in the animals.

A study of a low dose blend of celecoxib (Celebrex) and the cholesterol-lowering medication Lipitor found these "dramatically" limited the incidence of invasive and non-invasive colon adenocarcinomas.

"The combination of these drugs given to laboratory animal models inhibited 95 percent of the tumors that developed in untreated animals," said study author Dr. Bandaru Reddy, a research professor at Rutgers University's School of Pharmacy, in Piscataway, N.J. "When used together, the drugs were most effective at doses substantially lower than when used alone." The combination also had fewer side effects than either drug separately.

"Using a combination of low doses of these chemopreventive agents that have differing action may be the most effective way to maximize the anti-cancer effect of the drug while also minimizing toxicity or harmful side effects," Reddy said.

Reddy's animal studies were designed to model development of cancer in the human colon. The doses of the drug combination ingested by the experimental rats were the equivalent of 120 mg/day for celecoxib and 40 mg/day for Lipitor.

“These studies indicate that in combination at very low doses we increase the efficacy of the drugs while at the same time reduce the toxicity,” Reddy said.

Doses of Celebrex (celecoxib) which led to the FDA's call for the Black Box warning label were generally 400 to 800 mg/day--higher than the levels used in Reddy's studies.

Another colon cancer study, this one using high doses, found that Celebrex altered the genes of people at high risk for a hereditary form of colon cancer. Patients with this inherited disorder, known as Lynch Syndrome or hereditary nonpolyposis colon cancer or (HNPCC), are at higher risk of developing colorectal cancer and certain other types of cancer, such as ovarian or endometrial cancers. Only about three percent of all cases of colon cancer stem from this condition.

The scientists reported that many of the genes, whose expression is changed by Celebrex, were tied to the immune system and the inflammatory response. The results offer specific molecular evidence for how this drug may suppress the formation of colon polyps, which often serve as a marker for early colon cancer.

"Analysis of these celecoxib-induced changes in gene expression suggests that in the 'normal' colon, this COX-2 inhibitor may act directly or indirectly to suppress the immune response and early steps of inflammation," said Oleg Glebov, Ph.D., a cancer genetics researcher at the National Cancer Institute.

As described by the scientists, a set of 173 genes isolated in the normal mucosal lining of the colon is differentially expressed in patients genetically at risk Lynch Syndrome.

Glebov and his colleagues noted that patients taking higher doses of celecoxib (800 mg twice a day) experienced more dramatic effects than those on lower doses (200 mg twice a day). Specifically, the drug affected genes involved with cell signaling, cell adhesion, response to stress, TGF-beta signaling, and the regulation of cell death, or apoptosis.

"We found that treatment of patients with celecoxib led to changes in more than 1,400 genes in the healthy colon," Glebov said. "Of those genes, a specific set of 173 forms a signature portfolio that accurately identifies the colonic biopsies from patients taking the nonsteroidal anti-inflammatory drug (NSAID) celecoxib."

All of these studies come at a critical time for Merck, Pfizer and other Cox-2 inhibitor and NSAID manufacturers. In the USA, trials of Pfizer's Celebrex (celecoxib) were halted last December when patients taking the drug at moderately high levels suffered triple the normally expected number of heart attacks and strokes. The trials were testing Celebrex not as a painkiller but as a preventive against another rare colon cancer.

Celebrex looks quite promising for prevention of recurrent prostate cancer in men who have received primary treatment for this disease (Cancer Patients and Celebrex in Anti-Cancer Trials Nov 10, 2004), but cardiovascular effects have yet to be tracked and analyzed.

This month the FDA decided that Celebrex must carry a "Black Box" warning of risks of stomach bleeding and increased risks of heart attack and stroke. All non-steroidal antiflammatory drugs must also carry these warnings, FDA advised, plus labels to "remind patients of the limited dose and duration of treatment of these products in accordance with the package instructions."

In addition, FDA asked Pfizer "voluntarily" to pull Bextra (valdecoxib), another prescription Cox-2 painkiller, which on top of other hazards carries risk of rare but fatal skin conditions. This makes the second"voluntary" recall of a Cox-2 inhibitor since Merck pulled Vioxx from the market in fall 2004.

by J. Strax, April 20, 2005

Sources include AACR, BusinessWeekAsia, DocGuide, Canadian Press, Reuters.

Earlier publications by John Sudbø include: Chemoprevention: treatment of persons at high risk of cancer (2003)

Contributing to the study presented by Sudbø were J. Jack Lee and Scott M. Lippman, UT M. D. Anderson Cancer Center, Houston, Texas; Andrew J. Dannenberg, Weill Medical College of Cornell University, New York, N.Y.; Simone Sagen, Wanja Kildal, and Albrecht Reith, The Norwegian Radium Hospital, Oslo, Norway; Jon Mork, The National Hospital, Oslo, Norway; Ari Ristimaki, Helsinki University Central Hospital, Helsinki, Finland; and Asle Sudbo, Norwegian University of Science and Technology, Trondheim, Norway.