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Drug suppresses colon tumors in mouse model

Scientists at the Whitehead Institute for Biomedical Research have produced the first conclusive evidence that a natural chemical process, called DNA methylation, plays a causative role in the development of colon tumors.

The Whitehead scientists also showed that a preventive drug treatment to inhibit DNA methylation reduces the formation of precancerous tumors by more than 80 percent in a mouse model of inherited colon cancer. The results were published in the April 21 issue of Cell.

"While the drug we used to reduce the number of tumors in affected mice is too toxic for use as a preventive treatment in humans, 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," said Dr. Rudolf Jaenisch, one of the leaders of the Whitehead research group and a professor of biology at MIT.

People with familial adenomatous polyposis (FAP) may develop as many as 1,000 benign colorectal polyps before the age of 40. If they are not removed, some of these polyps progress to colon cancer. (Colon cancer is the second leading cause of cancer deaths in the United States; FAP accounts for about one percent of all colon cancers.) Currently, FAP is treated with surgery; in severe cases, the colon may have to be removed. A drug that could suppress polyp formation would represent a major advance in the prevention and treatment of this disease. The Whitehead study suggests an important new direction in the search for such a drug.

Dr. Jaenisch and his associates, including principal authors Peter W. Laird, Laurie Jackson-Grusby and Amin Fazeli, began their work with a very specific mouse model of FAP developed by Dr. William Dove's laboratory at the University of Wisconsin at Madison in 1990. 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 Whitehead researchers interbred the Min mice with a second mouse strain developed in Dr. Jaenisch's laboratory. These mice have a genetically induced shortage of an enzyme called DNA methyltransferase, which 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.

Influenced by existing theories about the development of colon cancer, the researchers expected that mice produced in the breeding experiments would have more polyps than Min mice in the control group. But to everyone's surprise, the opposite was true.

At 180 days, the Min mice with reduced DNA methyltransferase enzyme had 60 percent fewer polyps than the control Min mice. 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.

Scientists will now 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.

This work was funded by grants from the National Institutes of Health, the National Cancer Institute, the Damon Runyon-Walter Winchell Foundation and the Undergraduate Research Opportunities Program (UROP) at MIT.

The title of the Cell paper is "Suppression of Intestinal Neoplasia by DNA Hypomethylation."

A version of this article appeared in MIT Tech Talk on April 26, 1995.

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