A drug that was originally approved for its anti-inflammatory properties has quickly become the focus of a broad range of cancer trials that aim to establish the drugs effectiveness in preventing or treating nine different types of cancer.
By the time the U.S. Food and Drug Administration approved the COX-2 inhibitor celecoxib for polyp prevention in patients with familial adenomatous polyposis (FAP) in December 1999, clinical trials investigating the drugs potential to help prevent colorectal cancer and three other cancers were already in progress. Today, experts are optimistic that the drug may prove useful for cancer treatment as well.
"Here we have a drug that was designed to treat pain, made its foray into the cancer field as a prevention drug, and is now being fast-tracked into cancer therapy," said Andrew Dannenberg, M.D., director of cancer prevention and Erle-Roberts Family Professor of Medicine at New York Presbyterian Hospital and Weill Medical College of Cornell University.
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COX-2 inhibitors are already in clinical trials for the prevention of colorectal, oral, skin, esophageal, and non-small-cell lung cancers and for the treatment of cervical, prostate, and metastatic breast cancers. In addition, high levels of COX-2 have been found in gastric, liver, pancreatic, and biliary tumors. According to Raymond DuBois, M.D., Ph.D., director of Gastroenterology and Cancer Prevention and Mina C. Wallace Professor of Medicine and Cell Biology at Vanderbilt University, further investigation is needed to determine whether COX-2 is also present in ovarian and endometrial tumors, as some data indicate.
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Prevention Trials
Most of the prevention trials are enrolling patients who have premalignant conditions or are otherwise at high risk for cancer. (See table, p. 249.) The largest of these is a phase III trial with FAP patients, which began in March 2000. While celecoxib has been approved for use in reducing polyp number, it is not yet known whether this will translate into a reduced risk of colorectal cancer for these patients.
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Skin cancer is another promising target for prevention, with trials under way for patients with basal cell nevus syndrome and for patients with actinic keratoses. A third skin cancer prevention trial is the only prevention trial enrolling participants who have no elevated cancer risk.
A phase II trial enrolling tobacco smokers is investigating celecoxibs role in the prevention of non-small-cell lung cancer. COX-2 has been shown to play a role in the conversion of procarcinogens to carcinogens, including some of those found in tobacco. "For those individuals who cant or wont stop smoking, we may be able to intervene at this level," Dannenberg said.
The involvement of multiple pathways indicates that COX-2 inhibitors may be helpful not only in cancer prevention but in cancer treatment as well, Dannenberg said.
In fact, researchers have found that COX-2 inhibitors not only slow tumor growth in mice but that, when they are administered with standard chemotherapies, the combined effect of the two drugs is additive. "There is definitely the potential that addition of COX-2 inhibitors to standard chemotherapy will be helpful in humans," Dannenberg said.
David Gaffney, M.D., Ph.D., assistant professor and medical director of the Division of Radiation Therapy at the University of Utah, Salt Lake City, is the lead investigator on one of the first treatment trials using celecoxib, a phase I/II trial combining celecoxib with radiation plus fluorouracil and cisplatin for treatment of women with advanced cervical cancer.
Although all cervical tumors express COX-2 at some level, Gaffney pointed out that higher levels of expression are associated with worse prognoses. "Preliminary evidence suggests that inhibition of COX-2 sensitizes tumors to radiation without effect on normal tissue," Gaffney said, so he said he is hopeful that inhibition of COX-2 may improve the effectiveness of cervical cancer treatment.
Other treatment trials combining celecoxib with standard therapy target patients with prostate and metastatic breast cancerstwo cancers in which COX-2 levels are known to be elevated. However, COX-2 inhibitors may be useful treatment even for cancers in which this is not the case.
Combination Therapies
Wounded tissue expresses COX-2, and standard cancer therapies like paclitaxel and radiation clearly induce COX-2 expression. "Its a way for the body to protect itself," Dannenberg said. "Its a survival factor." This means that COX-2 inhibitors may be an effective adjuvant to these therapies regardless of the level of the enzyme prior to treatment. Trials that evaluate these combinations of therapy will be an important next step, Dannenberg noted.
Preclinical data suggest that COX-2 may also play a role in both gastric and pancreatic cancers. COX-2 is overexpressed in an overwhelming majority of pancreatic and gastric tumors as well as in precancerous gastric lesions.
"Theres been a lot of discussion about testing COX-2 inhibitors in combination with other therapies for pancreatic cancer, given how tough that disease is," Dannenberg said. Growth of gastric tumors in animals has been slowed using COX-2 inhibitors, indicating that they may be useful for treatment of this disease as well, but trials will be difficult because this cancer is so rare in the United States.
The majority of COX-2 inhibitor trials in progress are using celecoxib, marketed by Pfizer as Celebrex. Merck also has a COX-2 inhibitor, rofecoxib (Vioxx), in clinical trials for both prevention and treatment of colorectal cancer. Several other compounds have been shown to inhibit COX-2 in the laboratory, and both Dannenberg and DuBois said that they agree that there may be clinical advantages to using compounds other than celecoxib and rofecoxib in humans.
"[These drugs] were developed as anti-inflammatory agents, and all of the initial screens were based on inflammation assays. It may be worth taking some other compounds through an anticancer screening process to see if they would be more effective," DuBois said.
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