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9cRA Shown to Reverse Premaliagnant Changes in Ex-Smokers

9cRA Shown to Reverse Premaliagnant Changes in Ex-Smokers

ORLANDO - About half
of the new cases of lung cancer diagnosed each year occur in patients who have
already quit smoking. Treatment with oral doses of 9-cis-retinoic acid
(9cRA), a form of vitamin A, might help protect ex-smokers from previous damage
done to their lungs, said Jonathan M. Kurie, MD, Thoracic and Head and Neck
Medical Oncology, M.D. Anderson Cancer Center.

At the 38th Annual Meeting of the American Society of
Clinical Oncology (abstract 1177), Dr. Kurie presented data from a randomized,
placebo-controlled trial showing that 9cRA significantly increased expression
of the retinoic acid receptor- (RAR-) in former smokers. This effect was
associated with a significant decrease in the amount of squamous metaplasia in
bronchial biopsies and suggests that upregulating RAR- expression can, indeed,
reverse some of the lung damage that leads to cancer in former smokers.

Dr. Kurie conducted this National Cancer Institute-funded
study with his colleagues at M.D. Anderson, National Cancer Center Hospital,
Tokyo, and Southwestern Medical Center, Dallas.

"All chemoprevention trials in current smokers have been
negative or actually harmful. Beta-carotene, for example, increases conversion
of procarcinogens to carcinogens in smokers," Dr. Kurie said. "These harmful
effects are not seen in nonsmokers or former smokers. Since former smokers now
account for 50% of lung cancers, they are an important group for trials of
potentially protective agents."

Heavy smoking reduces expression of the RAR- receptor. Such
receptor loss makes cells unresponsive to normal growth regulator signals and
is associated with an increased risk of preneoplastic cellular changes. Loss of
RAR- expression is thought to be a useful biomarker for identifying cells
likely to become cancerous.

The researchers randomized 226 ex-smokers to 3 months of
treatment with one of three treatments: 9cRA, 13-cis-retinoic acid
(13cRA) plus alpha-tocopherol (a synthetic form of vitamin E), or placebo. All
subjects had smoked at least 20 pack-years and had stopped smoking at least 12
months before the trial.

Subjects had bronchoscopic biopsies at six predetermined
sites. Biopsies were done prior to treatment, after 3 months of treatment, and
3 months after the end of treatment. Biopsies were evaluated for loss of RAR-
expression and for squamous metaplasia or dysplasia.


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