• 2/1/2004
  • Snyder et al
  • Public Library of Science Biology

Restoring p53 protein function in mouse cancer models eliminates tumors and increases survival of the animals, according to a new study. Because a p53 mutation is one of the most common events in the development of cancer, the results could have implications for a wide variety of tumors.

Cancer often begins with mutations in tumor suppressor pathways. Tumor suppressor genes—such as p53—arrest cell growth and induce apoptosis (programmed cell death) in response to cellular stress, such as chromosomal damage. Cells with p53 mutations can escape these constraints, leading to the uncontrolled growth characteristic of “immortal” cancer cells. Nearly all types of tumors have mutations in the p53 pathway, many of them in the p53 gene itself.

Steven Dowdy, of the University of California at San Diego, and colleagues introduced modified p53 peptides (parts of the protein) into cancer cells. p53 works as a “transcriptional” activator that binds to specific gene sequences and triggers apoptosis in response to DNA damage. One region of the p53 protein, the C-terminal domain, facilitates DNA binding. In cancer cells, synthesized peptides (called p53C’) derived from this region can induce apoptosis by restoring function to p53 proteins with DNA-binding mutations.

To get p53C’ peptides into cancer cells, the scientists used a technique pioneered by Dowdy that delivers proteins into the cell interior. Testing the effectiveness of the peptide therapy on mouse strains that model human metastatic disease, the scientists found that mice treated with the p53C’ peptide showed a reduction in tumor mass and lived six times longer than mice treated with a control peptide or untreated mice, with some animals remaining disease-free more than 200 days after treatment.

The research was published in the February 2004 issue of the Public Library of Science Biology.

*The article (Snyder et al., PLoS Biology, 10.1371/journal.pbio.0020036) is available from PLoS Biology at http://www.plosbiology.org/.