A New Molecular Attack on Cancer

Finding could lead to refinement of cell death process

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By
HealthDay Reporter

FRIDAY, Jan. 2, 2004 (HealthDayNews) -- Pharmaceutical company scientists are reporting a promising approach to a problem that has baffled cancer researchers for almost a decade: How to fix a molecular waste-disposal system that goes wrong.

The molecule that has their attention is named p53, a protein designed to detect cells that are becoming cancerous and kick off the process of controlled cell death called apoptosis. To make sure that p53 doesn't kill good cells, it is controlled by another protein, MDM2.

Since the mid-1990s, researchers have known that MDM2 can interfere with attempts by p53 to kill cancerous cells, but no one has yet come up with a workable way to stop that interference.

Now researchers at Hoffmann-LaRoche Inc. report in the Jan. 2 issue of Science that they might have such a method: Tiny molecules designed to block the site that MDM2 uses to bind to p53. They call the molecules "nutlins," a name that might confuse those who don't know that the Hoffman-La Roche laboratory is in Nutley, N.J.

"There is a well-defined region on the surface of the molecule where the interaction takes place, a region of three amino acids," says Lyubomir T. Vassilev, a molecular oncologist who heads the research effort. "If we are ever going to target the protein-protein interaction, this one offers the best opportunity."

Vassilev and his colleagues came up with the nutlins by first getting detailed X-ray images of the binding site. Then they screened a huge library of synthetic chemicals to find some that can nestle in the site to stop the protein-protein interaction.

"For the first time, we are showing that a small molecule can actually bind to the MDM2 surface," Vassilev says.

The p53-MDM2 interaction plays a role in perhaps half of all solid tumors, he says. But there's a long way to go before nutlins can be shown to have any value as a cancer treatment. Other approaches have been tried without success, he notes, and "many companies are terminating projects because it turns out to be not so easy."

"The next step to see if the molecules are appropriate for clinical use is to use mice as models," Vassilev says. "A significant number of experiments need to be done to elucidate the value of this approach."

And success with animal tests would not necessarily guarantee positive results with human cancers, he adds, because "many things can occur in clinical trials that are not predicted."

"We don't know yet to what extent side effects will be tolerated," he says.

A careful balance must be achieved Vassilev says, so that p53 mounts the appropriate attack against cancer cells with a minimum of harm to normal cells.

"One cannot predict all that will happen," he says. "With the right molecules and lots of work ... we believe we have molecules that can do the job."

More information

A primer on p53 and cancer is offered by the Rockefeller University. For more on cancer, visit the American Cancer Society.

SOURCES: Lyubomir T. Vassilev, Ph.D., molecular oncologist, Hoffmann-LaRoche, Inc., Nutley, N.J.; Jan. 2, 2004, Science

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