DNA METHYLATION PROVIDES CANCER CLUE
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
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
"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
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
Transmitted: 95-05-01 21:29:56 EDT
Related information at other Web sites
A Primer on Nucleic Acids and Purine and Pyrimidine Metabolism at NetBiochem