Drug combination may fight breast cancer

Tests during the past 2 decades have indicated that retinoic acid can retard and even reverse some aberrant cell growth, a property that makes it remarkably effective against a deadly form of leukemia. The Food and Drug Administration approved that use of the compound, a chemical cousin to vitamin A, in 1995. Other tests have indicated it may also work against cancers of the mouth, skin, and lung.

Working with tumor cells, researchers in Austria now report that retinoic acid shows promise against breast cancer when introduced following a drug that thwarts a cell process called methylation. This one-two punch awakens a potent cancer-fighting gene called RAR-beta-2, which is found on chromosome 3, say the scientists.

Atom clusters called methyl groups often coat DNA. Such methylation seems to regulate certain genetic functions. When it runs amok, however, the process can silence DNA, keeping it from being transcribed into RNA to generate needed proteins. Indeed, methylation of the DNA that switches on RAR-beta-2 stops production of its cancer-fighting protein.

RAR-beta-2 normally encodes the protein that serves as the retinoic acid receptor. When retinoic acid binds to this protein on tumor cells, it can trigger the cells to commit suicide, slow their rapid growth, or resume healthy functions, says study coauthor Martin Hermann, a molecular biologist at the University of Innsbruck. If scientists could free RAR-beta-2 in breast cancer cells from the stultifying effects of methylation and then supply retinoic acid, they should be able to impede malignant growth, he and his colleagues theorized.

To test the effect of this two-part plan, the researchers examined cell lines grown from eight kinds of breast tumors. They treated some cells from each line with a demethylating agent, retinoic acid, or both. Other cells received no treatment.

Four of the eight cell lines made retinoic acid receptors only if treated with both drugs, the researchers report in the May 17 Journal of the National Cancer Institute. Another cell line produced the protein even without treatment, but it created more when exposed to both drugs. In the three other cell lines, the drugs had little effect.

The researchers also examined 16 breast tumors removed during mastectomies or lumpectomies. They found methylation of the RAR-beta-2 gene in six of these tumors. Knowing whether RAR-beta-2 is impaired by methylation in women with a high risk of breast cancer may help researchers select which ones might benefit from the drug combination, the researchers suggest.

Unfortunately, physicians can’t preventively treat people with the demethylators now available, notes Michael B. Sporn, a pharmacologist at Dartmouth Medical School in Hanover, N.H., in the same journal issue. However, they are being used against deadly cancers in some trials on patients, says Hermann’s Innsbruck colleague Martin Widschwendter.

The side effects of these agents are as severe as chemotherapy, says Widschwendter. “There thus is a major need for the development of less toxic demethylating agents . . . if we are to restore silenced [tumor] suppressor genes to useful activity,” Sporn says.