Protein repair: new compounds may help cells fight off cancer. (This Week).

Like a frontline soldier dozing on his rifle, a gene called p53 lies dormant in every cell. At the first signs of cancer, however, the gene springs into action. The protein that it encodes binds to the cell's DNA and initiates a chain reaction that usually leads to cell suicide--and thus stops cancer in its tracks.

In about half of all cancer cases, however, the gene is mutated. The result: faulty proteins that can't bind to DNA. Researcher are now identifying compounds that seem to enable even these defective proteins to initiate the anticancer chain reaction.

The latest such compound has been identified by scientists in Sweden and Russia. In the March Nature Medicine, they describe a synthetic molecule that restores anticancer function to mutant p53.

The researchers screened about 2,000 compounds in the lab to see which ones suppress growth of tumor cells that have mutated p53. They named the one that stood out PRIMA-1, an acronym for p53 reactivation and induction of massive apoptosis (cell suicide).

The scientists then implanted human bone tumors producing inactive p53 protein under the skin of 12 mice. After the tumors had grown for 3 days, the scientists gave nine of the mice PRIMA-1 for 3 days. Each animal received six doses of the compound either intravenously or by injection into the tumor. The other mice received inert injections. Because all the mice had been bred to have depleted immune systems, the scientists could credit any anticancer effects to PRIMA-1's influence on the p53 protein.

Although the researchers don't know how PRIMA-1 affects the p53 protein, the treatment drastically curbed tumor growth. After 59 days, the tumors in the three mice getting inert injections averaged 556 cubic millimeters, but in the animals treated with PRIMA-1, the tumors were considerably smaller, says study coauthor Klas G. Wiman, a molecular biologist at the Karolinska Institute in Stockholm. In the mice whose tumors were directly injected with the compound, tumor size averaged only 5 [mm.sup.3].

"This is a really nice finding," says Carol Prives, a molecular biologist at Columbia University.

In other work, Alan R. Fersht and his colleagues at Cambridge University in England report in the Jan. 22 Proceedings of the National Academy of Sciences that a synthetic compound called CDB3 binds neatly to mutant p53 protein. This action enabled p53 to bind to DNA in a test tube, which could reawaken the protein's antitumor function, say the researchers.

These and other recent studies expand the roll of protein-altering compounds that are promising drug candidates. The challenge will be for scientists to determine a dose that achieves an antitumor effect but avoids toxic side effects, Prives says.

The p53 restorers identified so far may also serve as signposts toward structurally similar molecules that might do the job even better, Wiman says.