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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