September 12, 1997

Anit-inflammatory drug’s ability to fight colon cancer studied

Anit-inflammatory drug's ability to fight colon cancer studied

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Dr. Raymond DuBois (right), with graduate student Chris Williams, is studying an anti-inflammatory drug's ability to fight colon cancer. (Photo by Donna Marie Jones)

Research begun in labs at the Vanderbilt Cancer Center is moving another step closer to a prevention for colon cancer.

A clinical trial involving Vanderbilt, M.D. Anderson in Houston and St. Mark's Hospital in London, England, is determining whether a drug being developed for arthritis and other inflammatory diseases can also help fight colon tumors in patients with an inherited form of the disease.

"It's very rewarding to see this research come this far," said Dr. Raymond N. DuBois Jr., associate professor of Medicine and Cell Biology. "We started with a very basic concept in cell culture studies. Now it's in the clinical arena, and it's all happened over a period of three or four years, so that's very exciting."

The aspirin-like drug, celocoxib, inhibits an enzyme called cyclooxygenase 2, or COX-2. Investigation of its use against colon cancer was prompted by earlier discoveries in DuBois' laboratory about the drug's potential role in cancer and the ability of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) to inhibit the enzyme.

These earlier findings concluded that:

€ levels of COX-2 are elevated in colon cancer cells;

€ normal intestinal cells that have been genetically manipulated to overproduce COX-2 are stickier than normal and resistant to dying at a normal rate. Both these properties could logically contribute to the likelihood of cancer.

€ when these cells were treated with aspirin-like drugs, which inhibit COX-2, they revert to normal consistency and regain the ability to die when they are supposed to do so.

Research elsewhere has demonstrated that people who take aspirin and other NSAIDS regularly have half the risk of developing colon cancer as do people not taking these medications.

The current study, for which enrollment began last December, targets patients with a rare disease called familial adenomatous polyposis. These patients have inherited a genetic mutation that causes them to develop numerous colon polyps that inevitably become malignant.

After treatment with the drug, patients are evaluated to determine whether there's been a reduction in the size and number of tumors, DuBois said.

The clinical work is being done at M.D. Anderson and Saint Mark's, both of which have sizable registries of patients with the rare disease. There are only about 5,000 people in the United States and about 3,000 in the United Kingdom who have the disease, DuBois said.

Samples from patients' tumors and normal intestinal tissue are being analyzed at VUMC in DuBois' lab and the lab of Dr. Jason D. Morrow, associate professor of Medicine and Pharmacology. DuBois analyzes the samples for levels of COX-2, while Morrow measures levels of prostaglandins, which are produced by the enzyme and which are believed to cause the biologic changes in the cells.

"This is an opportunity to determine in people whether prostaglandin levels are elevated in tumors," said Morrow, who has worked with DuBois on a number of basic science studies related to COX-2, prostaglandins and colon cancer.

"The important thing about this line of research is that clearly it has a direct clinical relevance. We've been able to take observations from the lab into the clinic and ask questions about how inhibition of cyclooxygenase might play a role in inhibiting the formation of colon polyps and tumors."

The study, which will enroll a total of 82 patients, is expected to take about a year. Earlier studies of the drug have found it to be well-tolerated, with few if any side effects.

While this particular trial is examining how the drug affects already established tumors, DuBois and his colleagues ultimately would like to investigate it in other patient populations to determine its preventive potential, he said.

Preliminary animal studies with a similar compound have been encouraging, DuBois said.

"There are nice animal models where you can give an animal a carcinogen and they ultimately develop tumors of the intestine," he said. "Another research group has shown that if they give a selective COX-2 inhibitor to the animal before they give the carcinogen, it completely prevents development of cancer."

If results from the current trial are positive, the next step might be to study the drug in patients who have had an intestinal polyp removed, he said. Then they could be given the drug to determine any effects on subsequent polyp formation.

"Another situation might be patients who've had a colon cancer removed surgically and who have no evidence of disease," he said. "They might be put on this drug to see if it affects recurrence.

"It might even be possible to take patients who've failed chemotherapy and give them this drug in combination with another chemotherapeutic agent to see if they have a response. We have nothing else to offer some of those patients."

DuBois said this line of research is a good example of the importance of continued emphasis on better understanding the basic biologic mechanisms that underlie cancer.

"We've tried to understand the basic mechanisms for how something like aspirin might prevent cancer," he said. "By doing that, we've been able to unravel a whole other pathway that has allowed for the development of a different drug that has fewer side effects.

"The added feature of this work is that it's looking at ways to prevent cancer from developing in the first place."