Chemical Cousin Of Vitamin A Restores Gene Function In Former Smokers

Although they don't have clear evidence that the three-month therapy using 9-cis retinoic acid (9-cis-RA) restored health to cells that were already precancerous, the researchers say the work demonstrates that "chemoprevention" of future lung cancer may be feasible.

"The drug we used acts to reverse a genetic abnormality associated with development of lung cancer," says Jonathan Kurie, M. D., an associate professor of medicine in the thoracic/head and neck medical oncology department. "The work is a proof of concept, suggesting that compounds like this may prove to have a protective effect against development of precancerous lesions."

The study, led by Kurie and Reuben Lotan, Ph.D., professor of thoracic/head and neck medical oncology, will be published in the February 5 issue of the Journal of the National Cancer Institute. The findings are important, Kurie says, because it is the first one to study chemoprevention in former smokers.

The 45 million people in the United States who have quit smoking have reduced their risk of developing lung cancer, but genetic damage caused by smoking does not immediately disappear, researchers say. Half of all newly-diagnosed lung cancer occurs in former smokers, and so investigators are trying to find a way to stop the genetic damage from turning into cancer.

"This work shows that we can restore the gatekeeper in those who have quit smoking," says co-author Waun Ki Hong, M.D., head of the Division of Cancer Medicine.

"It may be possible to reverse some of the genetic damage that has accumulated."

Hong, a recognized leader in the study of chemoprevention, has previously shown that a different vitamin A derivative known as 13-cis-retionic acid (13-cis-RA) can prevent development of head and neck cancer.

Retinoids are natural and synthetic compounds related to vitamin A (retinol) and retinoic acid (RA) is needed for normal function of the epithelial cells that line the lung. Retinoic acid activates retinoic acid receptors (RARs) that regulate cell growth, differentiation, and death.

Heavy smoking, however, is known to reduce levels of a key receptor, retinoic acid receptor beta (RAR-_). Because loss of RAR-_ has been linked to development of precancerous lesions in the lung - and thus is considered a biomarker of "preneoplasia" - Lotan said it was logical to look at whether retinoid therapy could restore expression of the protective protein receptor.

They randomized 226 patients who had stopped smoking for at least one year to one of three treatment arms for a daily oral treatment given over three months. One group received a placebo, or dummy, drug. A second group was given supplements of 9-cis-RA, which had been shown in laboratory work to bind to a number of different RARs, and so might be highly effective. The supplement has also been found to prevent development of breast cancer in lab animals. The third patient group received 13-cis-RA, the drug that has worked well in head and neck cancer, and it was combined with alpha-tocopherol (a synthetic form of vitamin E), in order to reduce toxicity known to be associated with 13-cis-RA therapy.

The researchers took lung biopsies from six predetermined sites in each patient before treatment, after the 3-month treatment period, and 3 months after treatment cessation. Kurie's team then analyzed the biopsies for histological abnormalities and for RAR-_ expression in the 177 patients who completed three months of therapy.

The results show that RAR-_ gene expression had increased in patients who received 9-cis-RA; the percentage of biopsies with RAR-_ protein expression increased from 69 percent to 76 percent, a statistically significant difference compared to the other two groups. Gene expression dropped from 75 percent to 69 percent in placebo-treated patients, and there was no substantial change in RAR-_ expression in patients taking 13-cis-RA.

The multidisciplinary research team also found a statistically significant reduction in the number of biopsies with potentially precancerous lesions known as metaplasia in the 9-cis-RA group (from 8 percent to 4.7 percent) compared to patients treated with 13-cis-RA (from 5.8 percent to 3.6 percent). But, compared to placebo (9.2 percent to 7.8 percent), neither retinoic treatment had a statistically significant effect on development of metaplasia in this study. "There was a decrease in precancerous lesions in the 9-cis-RA group, but it was not statistically significant compared to the patients who didn't receive a retinoic treatment," Kurie says.

Despite promising results, this form of vitamin A may not be the best drug for lung cancer prevention because of such side effects as headaches, skin rashes, and fatigue, Kurie says. A related form, LGD1069, is in clinical trials in the United States, and Kurie is testing celecoxib, one of the so-called "super-aspirin" drugs, to determine if it might help repair lung damage from cigarette smoking. Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) known as a COX-2 inhibitor, which works to ease inflammation without causing stomach ulcers and other side effects of similar drugs. Celecoxib has already been shown to reduce the number of precancerous intestinal polyps in patients with a rare colon cancer.

The study was supported by the National Cancer Institute and by the Rippel Foundation, the American Cancer Society, the National Foundation for Cancer Research, and by M. D. Anderson Cancer Center.