Tumor suicide: gene therapy makes cancer cells self-destruct.

More than 37,000 people in the United States will be diagnosed with pancreatic cancer this year, and nearly all of those cases will be untreatable. Now, scientists have developed a gene therapy that kills pancreatic tumors in mice by causing the tumor cells to commit suicide.

Gene therapies often use crippled viruses to deliver therapeutic genes into a patient's cells, but injecting these modified viruses into people can be risky. For example, a patient in a 1999 gene therapy trial died from a severe immune reaction that scientists suspect was caused by the delivery virus.

To avoid such problems, Mien-Chie Hung and his colleagues at the M.D. Anderson Cancer Center in Houston packaged a self-destruct gene inside microscopic bubbles called liposomes. These bubbles, measuring 100 to 200 nanometers across, are roughly the size of viruses and have surfaces made of fat molecules similar to those in cell membranes. When liposomes touch cells in a patient's body, they can easily fuse with a cell's membranes and dump their genetic cargo inside. There, the gene triggers the cells' natural self-destruct mechanisms, which normally swing into action to remove severely damaged cells.

To avoid adverse side effects, the scientists had to ensure that the gene would exert, its deadly influence only in cancerous cells. The team incorporated the self-destruct gene into a ring-shaped DNA molecule in such a way that the gene would become active only in the presence of a certain protein found exclusively in pancreatic-tumor cells. Although the liposome delivered this ring of DNA to cells throughout the animals' bodies, the killer gene affected only tumor cells.

"In terms of gene therapies for pancreatic cancer, this is by far the most impressive data because we designed the therapeutic gene to be active only in the tumor cells," Hung says.

In experiments on human cells in culture, the liposomes killed pancreatic cancer cells but spared healthy cells. The scientists then implanted human--pancreatic cancer ceils into mice and allowed tumors to develop. Treatment with the gene therapy shrank the tumors, and 50 percent of the treated mice survived at least 120 days with no detectable cancer. All the untreated mice died in less than 45 days. The researchers found no evidence of toxic side effects from the treatment, they report in the July Cancer Cell.

"I think this [study's] approach is unique in achieving both a strong effect and good specificity" for pancreatic cancer cells, comments Scott E. Kern, a pancreatic oncologist at Johns Hopkins University School of Medicine in Baltimore. However, Kern notes that only a small fraction of liposomes injected into the bloodstream will randomly find their way to the tumor cells, as occurred in the Hung team's mouse experiments.

Kern suggests that scaling up the therapy for people might require an additional way to target the liposomes to enter only tumor cells. Hung, however, believes that the current delivery system will work in people.