PHILADELPHIAPhysicians should approach the use of retinoids for
chemoprevention of aerodigestive cancers very carefully, warns a
research scientist who has been studying the use of natural and
synthetic vitamin A in animal models with esophageal cancer. The
studies have shown increased tumorigenicity among the animals treated
with the synthetic vitamin.
The rationale for use of retinoids as putative chemopreventive
agents comes from evidence in the literature over the last 2 decades
showing that, as a class, they play an important role in cell
proliferation, differentiation, and apoptosis, said Ashok
Gupta, MD, PhD, a research scientist with Dr. Gary Stoners
group at the School of Public Health, Ohio State University. He spoke
at the 5th International Congress of the Society for Nutritional
Oncology Adjuvant Therapy.
But the evidence for potential benefit from retinoids in
aerodigestive cancers is mixed, Dr. Gupta said. The benefit may vary
by cancer site, stage of disease, and type of retinoid used.
On the plus side, for example, retinoids have been shown to reverse
certain premalignant lesions in the oral cavity and metaplasia in the
lungs. But on the minus side, chronic heavy smokers given
beta-carotene in the NCIs Alpha Tocopherol Beta-Carotene (ATBC)
study in Finland showed an 18% increase in the incidence of clinical
and histologic lung cancer.
In the Beta-Carotene and Retinol Efficacy Trial (CARET),
beta-carotene was used in combination with retinol (vitamin A) in
18,500 workers, including 4,000 asbestos workers, some of them
smokers. The study had to be terminated 2 years early because of the
ATBC results and similar findings in the CARET study. The CARET
results showed a 28% increase in lung cancer among the asbestos
workers who smoked and were receiving beta-carotene.
Citing these and other findings, as well as his own research, Dr.
Gupta expressed concern that there may be some unpleasant surprises
ahead in clinical trials using retinoids. The reason, he believes, is
that, somehow, retinoids may make it easier for the body to
Dr. Gupta and his colleagues at Ohio State came to that conclusion by
studying esophageal cancer in animal models. They assessed the
chemopreventive potential of fenretinide [N-(4-hydroxyphe-nyl)
retinamide] (4-HPR), a synthetic
retinoid, and 9-cis-retinoic acid (9-cis-RA), a naturally
occurring retinoid, in rats with esophageal carcinogenesis induced by
At the end of 16 weeks, animals receiving a low-dose or a high-dose
4-HPR diet showed significantly enhanced esophageal tumorigenesis,
compared with animals on a control diet. In contrast, animals fed
9-cis-RA showed no significant increase in tumor multiplicity.
In vitro studies showed that dietary administration of 4-HPR
significantly increased the ability of esophageal explants from these
animals to metabolize NMBA. The researchers concluded that 4-HPR can
increase bioactivation of NMBA and cause enhanced tumorigenicity in
rat esophageal tissues.
Most carcinogens that people are exposed to are, by themselves,
inactive or inert, Dr. Gupta said. They have to be taken
up by the target cell, or in some instances by metabolizing organs
like the liver, and converted into active or reactive electrophiles
before they can attack the DNA and cause mutations.
Concern About Breast Cancer Trials
Dr. Gupta is especially concerned about breast cancer prevention
trials of retinoids. He said that animal studies similar to those his
group conducted in rat esophageal cancer have been performed in the
same rat strain with carcinogens that are specific to the breast.
When these animals diets were supplemented with 4-HPR, breast
cancer was inhibited.
The findings led to the use of 4-HPR in a phase I study and now in
phase II clinical trials for prevention of breast cancer. The
real problem is that there is a possibility that 4-HPR may actually
have differential effects on different tissues, Dr. Gupta
commented. Plus, you really do not have a control on what kind
of carcinogens the subjects are going to be exposed to.
Thus, Dr. Gupta concluded, there is a possibility that we may
have a few sur-prises in terms of retinoids and their clinical use as
putative chemopreventive agents. If you look at oral cavities, for
example, initial studies with other retinoids, such as retinyl
palmitate, actually show a significant increase in tumor incidence in
these model systems. There are similar results in tumors in the
trachea. So, in all, retinoids appear to be a mixed bag of goods.
The Physicians Health Study
Dr. Gupta noted that in the Physicians Health Study in which
more than 22,000 male US physicians supplemented their diet with
beta-carotene, there was no significant increase in lung cancer risk
after 12 years of follow-up. But, he pointed out, there was a much
lower overall beta-carotene content in the physicians diets
than in the ATBC study, and the incidence of smoking among the
physicians was very low.
Can we use a single agent or can we combine these agents to
really prevent the primary incidence and mortality of aerodigestive
cancer? he asked. I think we have just begun to approach
this issue, and it will probably take a significant number of
investigations before we really address this in terms of primary
disease of the lung and other aerodigestive cancers, Dr. Gupta