Gene Silencing Studies Yield Potential New Class of Anticancer Drug

Release Date:
4/16/2004
Contact:
Kirstie Saltsman
saltsmank@nigms.nih.gov

Everything from the genes you inherit to what you eat, the air you breathe, and how much you exercise influences the development of cancer. But the disease ultimately results from chemical changes to DNA that spur cells to grow and divide uncontrollably. One of these changes is called DNA methylation, which in normal cells "silences," or shuts off, genes that are not needed in particular cell types or under certain conditions.

In some cancer cells, however, abnormal DNA methylation shuts off tumor suppressor genes, which normally put the brakes on cell growth and division. Since turning these genes off opens the door to uncontrolled cell growth and cancer, scientists have long hoped that chemicals that inhibit DNA methylation would one day prove useful as anticancer drugs. But the toxicity and instability of these chemicals have dogged drug-development efforts.

Now, thanks to a study that began with a commonly studied laboratory fungus, a new DNA methylation inhibitor is under investigation as a potential anticancer drug. Molecular biologist Eric Selker, Ph.D., of the University of Oregon, Eugene, initially discovered that a molecule called zebularine reverses DNA methylation in the fungus. He went on to show that zebularine also reverses DNA methylation and reactivates a tumor suppressor gene in human bladder cancer cells grown in the laboratory. Selker then injected these cancer cells into mice and gave them zebularine orally. The molecule reduced tumor size in the mice, making zebularine the first methylation inhibitor to have such an effect in animals.

Zebularine is unique among the DNA methylation inhibitors that have been studied to date because it is chemically stable, can be administered orally, and appears to be minimally toxic. Its only side effect seems to be a slight weight loss in the mice given the chemical. These favorable properties suggest that zebularine may be a good candidate for drug development and that it could be a prototype for a new class of anticancer drugs. Selker's university has filed a patent on the potential uses of zebularine and is currently working to develop it into a marketable drug.