Expanded Role Seen for Retinoic Acid in Chemoprevention

NEW YORK—Researchers at Weill Cornell Medical College are investigating retinoic acid in the hope of extending its use in cancer chemoprevention as well as chemotherapy. Various vitamin A derivatives have already been shown to be useful in reversing premalignant changes such as leukoplakia and in treating pro-myelocytic leukemia.

“Retinoic acid is the most biologically potent of the retinoids, a master regulator of cell growth and differentiation,” Lorraine Gudas, PhD, professor of pharmacology, said at a media briefing sponsored by Weill Cornell.

Dr. Gudas explained that when a normal cell is bathed in a vitamin A medium, retinol is converted for storage as a retinyl ester. It is also converted into various metabolites, of which retinoic acid is only one. Retinoic acid zeroes in on the cell nucleus, where it binds to receptors (RAR and RXR) and is active in upreg-ulation of various genes. Three different types of proteins (alpha, beta, and gamma) have been identified for both RAR and RXR, she said.

Tumor cells do not store vitamin A. “The enzyme LRAT is not expressed so it cannot produce retinyl esters,” Dr. Gudas said. Her laboratory, in collaboration with Dr. David Nanus, found, for example, that normal kidney tissue had more than 10 times as much retinyl esters as renal tumor tissue from the same patient.

“Tumor cells are profoundly vitamin A deficient, which is why normal growth and differentiation do not occur,” she said. Treating this “vitamin A deficiency,” she noted, may lead to effective anticancer therapy. The challenge is to devise a delivery method for retinol that will overcome tumor cell resistance to retinol storage. One approach, she said, involves coating retinyl esters with a liposomal cover and injecting them directly into tumor cells.