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Everyday Drugs Show New Promise for Cancer
by Katie Prout Matias No one thinks much about the wonders of aspirin, that innocuous and bitter tasting little white pill. Did you know, for example, that it journeyed to the moon in 1969, or that it was actually prescribed 2,400 years ago by Hippocrates? He found that chewing on the bark of the willow tree, which contains the natural form of aspirin, relieved aches and fevers. Most impressive is that, in addition to combating arthritis and cardiovascular disease, aspirin may even have the power to prevent certain forms of cancer. Aspirin may not be the only common drug to have this unexpected and beneficial side effect; several other arthritis drugs, as well as some cholesterol drugs, have also been associated with a reduced incidence of cancer among long-term users in multiple retrospective studies. As part of the ongoing search for less toxic and less expensive cancer therapies, researchers at M. D. Anderson Cancer Center are investigating noncancer pharmaceuticals for their chemoprevention and cancer treatment potential. Chemoprevention with NSAIDs The old saying “Take two aspirin and call me in the morning” is now more or less being applied to patients at increased risk for colorectal cancer. Long-term daily aspirin use has been shown to cut colon polyp formation by as much as 35%, so many physicians are now prescribing low-dose aspirin to patients at high risk for colorectal cancer. “There is a huge body of epidemiologic data in support of aspirin, and aspirin is cheap as dirt,” said Patrick Lynch, M.D., J.D.,an associate professor in the Department of Gastrointestinal Medicine and Nutrition. “The only thing that gives me any reservation about recommending that everyone at increased risk for colorectal cancer take low-dose aspirin is the somewhat unpredictable side effects, gastrointestinal bleeding and ulcers.” In recent years, scientists have developed so-called “super aspirins,” the cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex). Often used in treating arthritis, the newer non-steroidal anti-inflammatory drugs are just as effective as aspirin at relieving pain but have fewer side effects. Aspirin’s side effects are a result of its nonspecific blocking action against two cyclooxygenase enzymes, COX-1, which is needed for healthy mucosal tissues, and COX-2, which is produced during inflammation and by precancerous tissues. Celecoxib blocks only COX-2, the one implicated in cancer risk. (See “Are COX-2 Inhibitors Safe?”). According to Banu Arun, M.D., an assistant professor in the Department of Breast Medical Oncology, who is studying the use of celecoxib in breast cancer prevention, COX-2 inhibitors have antiproliferative, apoptosis-increasing, and antiangiogenic effects. In her study, Dr. Arun wants to determine whether celecoxib might provide protection for women at increased risk of breast cancer who cannot take tamoxifen, the only preventive agent approved for this disease. Tamoxifen does not work in women with estrogen receptor–negative breast cancer, which is typically more aggressive and deadly than estrogen receptor–positive breast cancer. “In early studies, it was shown that COX-2 inhibitors prevent both of these types of breast cancer,” said Dr. Arun. “In our current prospective study, the patients are given the drug either for six or 12 months, and then we look at tissue endpoints. We are looking at markers in the breast associated with risk and evaluating the reversal of these markers. If we can show reversal of these markers, then that agent can be taken to the next step.” The markers they are looking at include cellular atypia, proliferation index, p53, HER2/neu, and apoptosis. Celecoxib has shown potential for use in preventing other types of cancer as well, including bladder, esophageal, skin, brain, lung, and head and neck cancer. The strongest evidence to date is in colorectal cancer prevention: In a study published in the New England Journal of Medicine in 2000, Dr. Lynch and others found that celecoxib reduced the number of polyps in patients with familial adenomatous polyposis (FAP), a hereditary disease that leads to the formation of hundreds to thousands of colon polyps and a 100% colorectal cancer rate by age 40 or 50. As a result of that study, the Food and Drug Administration approved celecoxib in 1999 as adjunct therapy for patients with FAP. More recently, Dr. Lynch completed a phase I study of celecoxib in children with FAP and plans to begin a larger, multicenter, international phase II/III trial this winter. “If we have a drug or drugs that could stabilize polyps and keep them from becoming cancerous or increasing in number and size, it might make them more manageable endoscopically,” he said. “We might be able to delay prophylactic removal of the colon, which is a major surgical procedure.” Revisiting cholesterol-lowering drugs Considering that an estimated 13 million Americans take statins to lower their cholesterol, recent findings that statins may reduce the risk of several kinds of cancer could result in these drugs inadvertently lowering the country’s overall cancer rates. Recent studies suggest that statins may bring about a 30% lower risk of breast cancer in postmenopausal women, a 58% lower risk of prostate cancer, and a 46% lower risk of colorectal cancer, as well as reduced pancreatic cancer and melanoma rates in laboratory animals. While multiple retrospective studies have looked at statins for chemoprevention, one researcher at M. D. Anderson is studying them for cancer therapy. In a study presented at the 2003 Annual Meeting of the American Association for Cancer Research, Khandan Keyomarsi, Ph.D., an associate professor in the Department of Experimental Radiation Oncology, showed that the prodrug form of lovastatin, one of six statins sold in the United States, stopped the uncontrolled growth of cancer cells in the laboratory. Dr. Keyomarsi has examined statins using breast, ovarian, and colorectal cancer cell lines and found comparable effects. “The pathway that is affected is pretty ubiquitous in all the different cancers,” said Dr. Keyomarsi. “We are basically affecting the brakes in the cell cycles, and this would compromise the growth of most cancer cells.” Statins lower cholesterol by shutting down an enzyme called HMG-CoA reductase. The drugs’ potential benefit in cancer could be a result of the fact that the prodrug form of the statins has a different target than HMG-CoA reductase, and that target affects the basic protein degradation machinery, leading to inhibition of cell growth. Statins’ anticancer effects could also be a direct result of their lowering cholesterol. “I think anything that would put that much stress on the body could have deleterious effects, whether it’s in the form of cancer or other diseases,” noted Dr. Keyomarsi. “But it’s also possible the mechanism has nothing to do with lowering cholesterol.” Indeed, the findings have been mixed on whether non-statin lipid-lowering drugs have the same anticancer effects as statins. If physicians were one day to prescribe statins for cancer prevention or therapy, they would have to take into consideration the sometimes severe and even fatal muscle problems that have been associated with these drugs. As with aspirin or celecoxib, patients would likely have to take the drugs indefinitely for chemoprevention. Randomized, controlled, prospective clinical trials are needed to confirm whether statins can truly prevent or treat cancer. “Because there’s enough anecdotal evidence out there and enough mechanistic evidence to suggest that these agents could and should be used as chemoprevention agents, there should be clinical trials,” said Dr. Keyomarsi. On the horizon Researchers at M. D. Anderson and the National Cancer Institute are now setting their sights on another noncancer drug for the possible prevention of cancer: rosiglitazone. Used to treat type II diabetes, rosiglitazone helps the body use insulin more efficiently. Very early preclinical studies have shown that it also appears to slow the growth of tumors and inhibit angiogenesis. According to Dr. Arun, she and her colleagues are teaming up with Karen Lu, M.D., from the Department of Gynecologic Oncology, to conduct a clinical trial of rosiglitazone in breast and uterine cancer prevention. “Not only for breast but also for some other cell lines, it was found that the drug decreases the proliferation of tumor cells, which in turn is associated with decreased risk of cancer,” said Dr. Arun. “We are going to study this drug in patients who have insulin resistance. Insulin resistance has been linked to an increased risk of uterine as well as breast cancer, so these patient populations are actually ideal to study with this drug.” While the idea that relatively nontoxic drugs that so many people are already using could be preventing some kinds of cancer is doubtless exciting, Dr. Lynch urged caution in viewing them as a cure-all. “We don’t have any magic bullets,” he said. “We have agents that can reduce risk, but the long-term benefits or risks are not known. The need for periodic surveillance has not gone away. The search for newer, better drugs continues.” Sage caution, given the recent lessons learned from Vioxx.For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, December 2004 issue:
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