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Results in former smokers treated with 9-cis-retinoic acid show promise that chemoprevention of lung cancer may be possible

Expression of a protein protective against lung cancer was restored in former smokers who were treated with 9-cis-retinoic acid, according to an article in the February 5th issue of the Journal of the National Cancer Institute. Although there is no evidence yet that the 3-month therapy with the Vitamin A derivative restored health to precancerous cells, the researchers say the work demonstrates that chemoprevention of lung cancer may be possible.

"The drug we used acts to reverse a genetic abnormality associated with development of lung cancer," said Jonathan Kurie, M.D., lead author of the study. "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 current study was the first to study chemoprevention in former smokers. "This work shows that we can restore the gatekeeper in those who have quit smoking," said coauthor Waun Ki Hong, M.D., also of the National Cancer Institute. "It may be possible to reverse some of the genetic damage that has accumulated."

Hong, a recognized leader in the study of chemoprevention, had previously shown that 13-cis-retinoic acid can prevent development of cancers of the head and neck. Retinoic acid activates receptors that regulate cell growth, differentiation, and apoptosis.

Heavy smoking is known to reduce levels of the key receptor called retinoic acid receptor beta. Because loss of this receptor has been linked to development of precancerous lesions in the lung, the research team concluded it was logical to look at whether retinoid therapy could restore expression of the protective protein receptor.

The team randomized 226 patients who had stopped smoking for at least 1 year to 1 of 3 treatment arms for a daily oral treatment given over 3 months. One group received a placebo. The second group was given 9-cis-retinoic acid, which had been shown in laboratory work to bind to a number of different cell receptors and to prevent breast cancer in lab animals. The third patient group received 13-cis-retinoic acid combined with alpha-tocopherol in order to reduce toxicity associated with 13-cis-retinoic acid therapy.

The researchers took lung biopsies from 6 predetermined sites in each patient before treatment, after the 3-month treatment period, and 3 months after treatment cessation. The team analyzed the biopsy samples for histological abnormalities and for retinoic acid receptor beta expression in the 177 patients who completed 3 months of therapy.

Expression of the gene for the receptor increased in patients who received 9-cis-retinoic acid from 69 percent at baseline to 76 percent, a statistically significant difference compared with findings for the other two groups. Gene expression dropped from 75 percent to 69 percent in placebo-treated patients, and there was no substantial change in expression in patients who took 13-cis-retinoic acid.

The multidisciplinary research team also found a statistically significant reduction in the number of biopsies with metaplastic lesions in tissue samples from the patients treated with 9-cis-retinoic acid (from 8 percent at baseline to 4.7 percent after treatment). However, the reduction in metaplasia was not significant compared with reductions in the 13-cis-retinoic acid group (from 5.8 percent to 3.6 percent) or with the placebo group (9.2 percent to 7.8 percent).

Despite promising results, 9-cis-retinoic acid’s potential as a chemopreventative may be limited due to side effects such as headaches, skin rashes, and fatigue, according to Kurie. He noted that LGD1069, a related compound, is in clinical trials in the U.S. His group is testing celecoxib, a COX-2 inhibitor in the nonsteroidal anti-inflammatory drug class that has been shown to reduce the number of adenomatous intestinal polyps in patients with familial adenomatous polyposis


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