Drug blockades blood vessels' energy.

Last year, a media frenzy over a new class of drugs raised hopes of a cure for cancer. Researchers have now discovered how one of these drugs may work. This knowledge could guide the development of smaller, more easily produced agents to eradicate tumors.

Angiostatin, one of the promising anticancer drugs, starves mouse tumors by blocking the growth of blood vessels that sustain them (SN: 5/2/98, p. 286). Scientists didn't know the cellular mechanism underlying the drug's action. The new discovery suggests that angiostatin deprives blood vessel cells of the energy that they need to proliferate.

Angiostatin sticks to and gums up an enzyme on the cells that line blood vessels, researchers from Duke University Medical Center in Durham, N.C., and their collaborators report in the March 16 Proceedings of the National Academy of Sciences. This enzyme produces adenosine triphosphate (ATP), the compound that cells break down to obtain energy.

Until now, the enzyme, called ATP synthase, had been found only in mitochondria, the energy-generating capsules that reside within cells. The scientists double- and triple-checked their results to make sure that the enzyme indeed coated the blood vessel cells, which they had extracted from human umbilical cord blood.

"I'd wager no one would have guessed that," says Duke biochemist Gordon G. Hammes, who studied the enzyme when it was first examined 30 years ago.

Although surprising, the finding "fits what's going on in the tumor microenvironment," says the study's lead author, Tammy L. Moser from Duke. Blood vessel cells are able to grow and multiply even in the harsh, oxygen-depleted environment of a cancerous tumor. By creating their own pools of ATP, says study collaborator Salvatore V. Pizzo of Duke, the blood vessel cells survive where other cells die.

Angiostatin, by putting the squeeze on the blood vessel cells' source of energy, starves the vessels, whose absence in turn starves the tumor.

Although the drug has raised many hopes, it's difficult to produce. The business end of angiostatin is folded up in pretzel-shaped "kringles," named for their resemblance to Danish sugar cookies, says Pizzo. "The problem is that it's very difficult to produce angiostatin in its native [structure]."

Knowing angiostatin's target enzyme, researchers may be able to create less contorted drugs with the same power. "Anytime you find a binding protein for a therapeutic agent, you immediately think: Could you engineer a smaller molecule that ... could substitute for or mimic the agent?" says Judah Folkman of Children's Hospital in Boston, who pioneered the study of blood vessel-growth inhibitors to combat cancer.

This class of drugs continues to gain new members. Other Boston researchers report in the same issue of PNAS that they isolated a compound from human cartilage that inhibits blood vessel growth in mice.