Searching for clues in smokers’ lungs

Some of the most interesting discoveries in medicine occur when drugs used to treat one disorder are found useful for an entirely different condition.

Doctors discovered in the mid-1980s, for example, that aspirin can help prevent heart attacks, leading to widespread use of the inexpensive drug in many adults. Now researchers are testing an arthritis drug, Celebrex, to see if the medication can prevent lung cancer. The study is based on the emerging hypothesis that, like arthritis, cancer is a disease involving inflammation.

A medication that lowers the risk of cancer in smokers and ex-smokers could dramatically reduce lung cancer death rates in America, says Dr. Jenny Mao, an assistant adjunct professor at UCLA’s Jonsson Comprehensive Cancer Center and lead investigator of the study. The majority of people diagnosed with lung cancer today are former smokers, she says.

“The most important thing people can do is quit smoking. But smoking cessation, by itself, doesn’t completely eliminate the risk of lung cancer,” she says. “That is one of the reasons we are looking at new frontiers in prevention and at early cancer detection.”

Mao is exploring the theory that an enzyme called COX-2, already known to play a role in arthritis, is also involved in many cancers. The enzyme is responsible for the overproduction of prostaglandins, substances that cause inflammation. In the mid-1990s, Mao’s research with Dr. Steven Dubinett at UCLA was the first to show the presence of the COX-2 enzyme in lung cancer cells.

Celebrex inhibits COX-2 enzymes. Studies have shown that people who take nonsteroidal anti-inflammatory drugs, such as Celebrex, tend to have reduced rates of certain cancers, including cancer of the lungs, Mao says. The U.S. Food and Drug Administration already has approved Celebrex for treatment of people with familial polyposis, an inherited disease in which colon polyps inevitably progress to colon cancer.

Studies also have shown that COX-2 inhibitors reduce lung cancer tumor growth in animals and kill tumor cells in the test tube. The research is promising enough to begin studies in lung cancer patients. In an earlier study with just 20 heavy smokers, Celebrex was found to suppress the production of prostaglandins.

The new study will involve 180 former smokers who are at high risk of lung cancer or who have already had surgically removed nonsmall cell lung cancer, the most common form of lung cancer. Patients will be randomly assigned to receive either Celebrex followed by a placebo, or the placebo followed by Celebrex, for six-month intervals. Researchers will track the patients for four years to look for changes in prostaglandin production and bronchial cells.

“There is a lot of commonality between lung cancer and inflammation,” Mao says. “Smokers have a tremendous amount of inflammation in the airways. That could account for the whole cancer process.”

Researchers are eager to find ways to thwart lung cancer in high-risk patients, says Dr. Glenn Rosen, a spokesman for the American Lung Assn. of California and an associate professor of medicine at Stanford University in Palo Alto.

“The animal data suggest that COX-2 does play a role in the progress of cancer,” Rosen says. “Whether it will work to prevent the development of cancer is less clear. It’s not clear what the exact role of prostaglandins is in the genesis of these tumors. But this is a logical study to do.”

While the work holds promise, Mao cautions against smokers or ex-smokers taking COX-2 inhibitors on their own. Previous attempts to find something that can prevent lung cancer have failed, she notes, including the well-known trial of beta carotene in smokers; the supplement actually caused a slight increase in lung cancer risk.

“The dose we use is higher than the dose used for arthritis,” she says. “And obviously we want to make sure there are no side effects.”

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A high-tech tool for looking at lungs

Patients enrolled in the Celebrex study will be monitored regularly for signs of precancerous changes in their lungs. To do so, doctors at UCLA’s Jonsson Comprehensive Cancer Center will use the best technology available: fluorescence bronchoscopy.

During the procedure, doctors insert a flexible tube into the airways and use a special laser light to look for changes in tissue. Although fluorescence bronchoscopy is similar to traditional bronchoscopy in many ways, the laser light improves doctors’ ability to detect differences between normal cells and cancerous cells by about 50% over traditional bronchoscopy, says Dr. Jenny Mao.

Fluorescence bronchoscopy is used in only about 60 to 80 medical centers worldwide.

-- Shari Roan