By Sean Henahan, Access Excellence

CAMBRIDGE, Mass. - New evidence linking DNA methylation and colon cancer may offer a new way to treat this common malignancy, reported a team of researchers from the Whitehead Institute for Biomedical Research.

The current research centers around an inherited from of colon tumor disease known as familial adenomatous polyposis. Patients with this disease may develop as many as 1,000 benign colorectal polyps before the age of 40. If these polyps are not removed surgically, some of them will progress to colon cancer.

The researchers began their studies with a very specific mouse model of FAP. These mice, called Min mice, have a mutation in the mouse equivalent of the human gene responsible for FAP. They develop 100 or more intestinal polyps in the first 6 months of life, thus providing an ideal system for studying the origins of human colon tumors.

The researchers interbred the Min mice with a second mouse strain bred with a genetically induced shortage of an enzyme called DNA methyltransferase. This enzyme adds methyl groups to DNA (methyl groups are composed of one carbon atom and three hydrogen atoms). The addition of methyl groups to DNA alters the activity of genes within the DNA molecule.

Based on current theories regarding the development of colon cancer, the researchers expected that mice produced in the breeding experiments would have more polyps than control Min mice. Much to the team's surprise, the opposite proved true. At 180 days, the Min mice with reduced DNA methyltransferase enzyme had 60 percent fewer polyps than the control Min mice.

The scientists also showed that a preventive drug treatment to inhibit DNA methylation reduced the formation of precancerous tumors in the mouse model. When the DNA methyltransferase levels in the test mice were reduced even further using a drug, 5-aza-2'-deoxycytidine (5-aza-dC), known to inhibit the enzyme, the number of polyps was reduced by 98 percent. In Min mice with normal DNA methyltransferase genes (analogous to human patients with the precancerous stage of familial adenomatous polyposis), 5-aza-dC treatment alone produced an 80 percent reduction in polyp formation.

"While the drug we used to reduce the number of tumors in affected mice is too toxic for use as a preventive treatment in human beings, our results indicate that it may be possible to design a less toxic analog of the drug that would decrease the incidence of precancerous growths in patients with familial adenomatous polyposis," says Dr. Rudolf Jaenisch, one of the leaders of the Whitehead research group and a professor of biology at the Massachusetts Institute of Technology.

The next step will be to explore whether it is possible to safely inhibit DNA methyltransferase activity in cells lining the human colon, with the long-term goal of suppressing polyp formation in patients with familial adenomatous polyposis.

Colon cancer is the second leading cause of cancer deaths in the United States. FAP accounts for about 1 percent of all colon cancers. A drug that could suppress polyp formation would represent a major advance in the prevention and treatment of this disease.

For more information on this study see- Cell, 4/21/95, Jaenisch et al. "Suppression of Intestinal Neoplasia by DNA Hypomethylation."