Novel Substance to Re-Program Tumor Cells
Tumor cells often silence growth-inhibiting genes by chemically tagging specific building blocks of DNA. DKFZ scientists have now synthesized a substance that reverses these alterations.
The expression of genes is regulated at different levels. One way, which has captured the attention of scientists in the past few years, is the addition of small hydrocarbon compounds called methyl groups to the cytosine building blocks of DNA. This process, called DNA methylation, turns off (“silences”) genes or at least represses their activity.
In cancer cells, the genes inactivated by methylation are often those whose task it is to protect the cell from uncontrolled growth, or tumor suppressor genes. Therefore, cancer researchers were aiming to find a way to prevent over-methylation. In the process, they concentrated on methyltransferases, i.e., enzymes that are responsible for transferring methyl groups. By computer-assisted modeling, scientists headed by Dr. Frank Lyko at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg were able to generate three-dimensional images of methyltransferases and to use these models for deriving the structure of a perfectly fitting inhibitor.
In experiments in the culture dish, the inhibitor, dubbed RG108, reduces the activity of methyltransferases in various cancer cells. Treatment with RG108 was found to significantly slow down the rate of cell division in a colorectal cancer cell line. The scientists were able to show that the degree of methylation of different tumor suppressor genes decreased and, thus, the protecting genes were reactivated. However, other DNA areas whose methylation pattern is believed to be relevant for chromosome stability were not affected by RG108.
“Fortunately, RG108 is only mildly toxic – quite opposed to other available inhibitors of methyltransferases,” said Lyko. “Thus, we now have a substance that has the potential to become the starting point for developing a whole new class of anti-cancer drugs.”
Bodo Brueckner, Regine Garcia Boy, Pawel Siedlecki, Tanja Musch, H. Christian Kliem, Piotr Zielenkiewicz, Sandor Suhai, Manfred Wiessler, and Frank Lyko: Epigenetic Reactivation of Tumor Suppressor Genes by a Novel Small-Molecule Inhibitor of Human DNA Methyltransferases. Cancer Research, July 15, 2005
With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.
To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
