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Researchers use gene therapy to starve tumors
By Bijal P. Trivedi

One way to stop a tumor from growing and spreading is to cut off its food and oxygen supply by blocking the growth of new blood vessels that feed it. Controlling blood vessel formation, a process called angiogenesis, could radically improve treatments for cancer, heart disease and wound healing. In a new study researchers at the Salk Institute, in La Jolla, CA, are using gene therapy to deliver anti-angiogenesis molecules.

Before endothelial cells (ECs), the cells that form capillaries and blood vessels, can invade and infiltrate a new area they must tunnel through the mesh-like matrix that exists between all cells and holds them in place. ECs secrete an enzyme called metalloproteinase 2 (MMP-2) that works as a molecular machete, hacking through the matrix and clearing the way for blood vessels. Once a path has been cleared the cells are free to form vessels. Stop MMP-2 and you stop angiogenesis.

The body switches off angiogenesis using a little molecule called PEX that stops MMP-2 from working. Now Alexander Pfeifer and his colleagues are encasing the PEX gene inside a virus and injecting it into the site surrounding the tumor. The idea is that the virus infects and delivers the PEX gene to the cells near the tumor. Each cell then produces PEX that will stop new blood vessels from growing.

Pfeifer has tested PEX in vitro. "If you put endothelial cells on a synthetic matrix they immediately start forming vessels, real capillary structures, it's just what they do," says Pfeifer. But when the cells are infected with the PEX-containing virus, they lose this ability.

In another experiment, human melanoma cells were implanted into 25 mice and allowed to grow. Five days after implantation half of the mice were given injections of viral-encased PEX and others were given a placebo gene. After 15 days animals that received PEX had tumors that were 64 percent smaller than tumors from mice that received the placebo. When the researchers examined the tumors they contained 56 percent fewer and smaller blood vessels.

Pfeifer intends to test the effects of PEX on other tumor types. Colon carcinomas are high on Pfeifer's list. "In many cases colon cancer is easily treated with surgery. But still many patients die because the cancer has spread to the liver. We want to see whether we can inhibit cancer spreading to the liver using PEX," says Pfeifer. There are good mouse models of colon cancer, which the group intends to use for future experiments.

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Pfeifer, A. et al. Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. Proc Natl Acad Sci USA, Early Edition (October 17, 2000).

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