NSAIDs add cancer to the arsenal of protection
NSAIDs add cancer to the arsenal of protection
Anticarcinogenic activity in COX-2 inhibitors
An aspirin, or an ibuprofen, may be better than an apple at keeping the physician away.
Recent animal studies at The Ohio State Univer-sity in Columbus show nonsteroidal anti-inflammatory drugs (NSAIDs), including prescription cyclooxygenase 2 (COX-2) inhibitors, have what researchers are calling "tremendously exciting" potential to prevent and treat breast cancer.1
The cardioprotective effects of NSAIDs are part of the standard of health care in America today, but their benefits against various types of cancers have, until recently, been less than definitive. Now a growing body of evidence points to a powerful anticarcinogenic effect in over-the-counter NSAIDs and in prescription COX-2 inhibitors.
"The big picture is that there have been three independent human studies that show a 40% to 50% reduction in breast cancer and a 65% to 70% reduction in prostate cancer among people who take aspirin or ibuprofen on a regular basis," says Randall Harris, MD, PhD, professor of epidemiology at Ohio State. "That alone is worthy of our attention."
Harris’s rat studies show, for the first time, a powerful risk reduction with the COX-2 inhibitor celecoxib (brand name Celebrex): a 67% decrease in breast tumor incidence and an 81% decrease in tumor size.
"NSAIDS appear to inhibit the carcinogenic process by interrupting the mutagenic effects of cell proliferation," says Harris. "Somehow cancer cells seem to become immortalized. The normal death cycle of cells is interrupted. NSAIDs somehow inhibit the [COX-2] mechanism, which proliferates in breast tissue in patients with breast cancer, thereby restoring the normal cell life cycle."
The COX-2 protein abundance causes a prostaglandin cascade, a flow of biochemicals that fight viral and bacterial invaders and initiate the immune response, says Harris. NSAIDs somehow turn off the prostaglandin cascade.
COX-2 inhibitors commonly are used to treat arthritis, but their effectiveness against cancer has not yet been tested in human trials. Harris and his colleagues also used ibuprofen in the trial and found a strong positive anticarcinogenic effect with a 40% reduction in the incidence of malignant breast tumors. "This has tremendous potential and the drug companies are very interested in it," says Harris. "Ten percent to 20% of all women 50 and older use NSAIDs on a regular basis. Not only are these drugs potentially important for breast cancer prevention and control, they also may have significant value in the prevention and therapy of other cancers, too, such as cancers of the colon, lung, and prostate."
Gastrointestinal bleeding is cause for concern
Gastrointestinal (GI) bleeding is a serious concern for patients taking NSAIDs, particularly aspirin, on a regular basis, says Michael Thun, MD, vice president of epidemiology and surveillance research for the American Cancer Society in Atlanta. Thun, who personally has conducted several studies on NSAIDs and cancer, says GI bleeds are not generally a problem in low-risk patients, but they become a serious concern in intermediate risk patients: those with high cholesterol and hypertension.2,3
"Then you start to just about even out the risk of GI bleeds vs. the events you may be preventing, even with a baby aspirin," says Thun. "In heart disease, serious GI bleeds are not uncommon, just about as common as the heart attack you’re trying to prevent."
Cancer research lags far behind heart research on the benefits of NSAIDs, making a general recommendation for prophylactic use of NSAIDs premature, says Thun. "The only proven clinical trial shows effectiveness against colorectal cancer, plus the exact mechanism and the lowest effective dosage have not yet been established," he says.
Thun says that doesn’t mean there isn’t great potential for the use of NSAIDs to prevent breast cancer. "The evidence that NSAIDs may be of benefit against breast cancer is much weaker and less consistent that research in other types of cancers. It just means we need to be sure the benefits outweigh the risk."
Neither the American Cancer Society in Atlanta nor few other health organizations currently recommend the general public take aspirin or other NSAIDs for cancer protection. Two groups, the Dallas-based American Heart Association and the American Diabetes Association in Alexandria, VA, however, recommend aspirin use for its cardioprotective benefits.
Harris says his research has shown reduced risk of GI bleeds from ibuprofen and, in his rat study, no incidence of GI bleeding, weight loss, or ulcers associated with celecoxib.
He says there is "always a downside" to the benefits of a drug, but, he adds, "A dose of 345 mg of aspirin [one adult aspirin] or 200 mg of ibuprofen is not harmful to most people over 50, if it is taken with physician knowledge and monitored. Most people who would have these side effects would already know they have this problem."
Celecoxib has been approved to suppress pre-malignant adenomatous polyps in patients with familial adenomatous polyposis, a rare condition that leads to colon cancer if preventive surgery is not performed.
Two recent British studies present conflicting reports on aspirin and the risk of developing breast cancer. One population-based study, looking at 28,000 women, found a 25% reduced risk of breast cancer for women using NSAIDs the most. Among women who used NSAIDs the most, if they did develop breast cancer, they tended to have smaller cancers and lower risk of metastasis if they used significant amounts of the drugs in the years before they were diagnosed.4
A conflicting study showed no effectiveness of aspirin against breast cancer but did show a lower risk of developing cancers of the esophagus, colon, and rectum among NSAID users.5
Finally, another British study that suggests aspirin inhibits COX-2 production in patients with prostate cancer. COX-2 levels become overactive in prostate cancer cells, occurring at four times the amount found in normal prostate cells, researchers said.6
References
1. Harris R, Alshafie G, Abou-Issa H. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 2000; 60(8):2,101-2,103.
2. Thun M. Aspirin and gastrointestinal cancer. Adv Exp Med Bio 1997; 400A:395-402.
3. Thun MJ. NSAID use and decreased risk of gastrointestinal cancers. Gastrointerol Clin North Am 1996; 25(2):333-348.
4. Heath C Jr., Thun M, Greenberg E. Non-steroidal anti-inflammatory drugs and human cancer, report of an interdisciplinary workshop. Cancer 1994; 74(10): 2,885-2,888.
5. Langman MJS, Chang KK, Gilman EA, et al. Effect of anti-inflammatory drugs on overall risk of common cancer: Case-control study in general practice research database. BMJ 2000; 320:1,642-1,646.
6. Sharpe CR, Collett J-P, McNutt M, et al. Nested case-control study of the effects of non-steroidal anti-inflammatory drugs on breast cancer risk and stage. Br J Cancer 2000; 83(1):112-120.
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