Use Caution in Retinoid Chemoprevention Trials

PHILADELPHIA—Physicians 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 Stoner’s 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 NCI’s 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 metabolize carcinogens.

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 N-nitrosome-thylbenzylamine (NMBA).

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 concluded.