Compound inhibits vessel growth, cancer.

Compound inhibits vessel growth, cancer

Using a genetically engineered protein that blocks the formation of new blood vessels, scientists have successfully inhibited the growth of cancerous tumors in mice. The work provides some of the clearest evidence yet that physicians may someday starve solid tumors to death with drugs that cut off a cancer's blood supply.

Twenty years ago, Harvard University's Judah Folkman proposed that tumor cells somehow trigger angiogenesis -- the growth of new blood vessels -- to fulfill their ravenous appetites and to wash away their accumulated wastes. Scientists have since identified several tumor-secreted factors that cause specialized cells, called endothelial cells, to organize into such capillary "water and sewage lines" in tumorous neighborhoods within the body. But the search for anti-angiogenic factors -- which would inhibit vessel formation -- has progressed slowly. Until recently, the few candidates studied in cell cultures and in animals have shown worrisome toxicity at concentrations that suppress angiogenesis.

Earlier this year, researchers at Repligen Corp. in Cambridge, Mass., showed that a genetically engineered version of a protein normally found in human platelets inhibited angiogenesis when applied to chick embryo membranes. They suggested that the protein, platelet factor-4 (PF4), had potential as a tumor-starving agent. Now, in the May 16 JOURNAL OF THE NATIONAL CANCER INSTITUTE, the researchers prove their hypothesis true.

Repligen scientists Richard J. Sharpe, Theodore E. Maione and their co-workers transplanted mouse melanoma cells and human colon carcinoma cells into mice, then compared tumor growth in mice that did and did not receive daily PF4 injections. The compound prevented the cancer cells from growing into tumors, the team reports.

Although a few other anti-angiogenic molecules have suppressed tumor growth in animal experiments, they have for the most part triggered a wide array of biochemical side effects. In contrast, experiments so far suggest that PF4 does nothing but prevent the local migration and proliferation of vessel-forming endothelial cells. Since new vessel formation is virtually absent in adults except during wound healing or following ovulation, the researchers anticipate few ill effects from angiogenesis suppression in cancer patients.

Maione says his group is now experimenting with an altered version of PF4 that persists longer in the blood than the current version. If further experiments confirm its value, he says, the team will seek FDA permission this year to give it to people with Kaposi's sarcoma, a cancer-like proliferation of endothelial cells.

"We're finally learning the rules of anti-angiogenesis," says Folkman, who is looking into a promising anti-angiogenic substance derived from a fungus. In addition, Noel P. Bouck of the Northwestern University Medical and Dental Schools in Chicago says she and her colleagues will soon publish details about an anti-angiogenic protein they discovered in blood platelets last year. And Harvard's Robert S. Langer and Marsha A. Moses will describe a cartilage-derived anti-angiogenic factor in SCIENCE this summer.