Angiostatin and endostatin have been among the most exciting items in cancer research over the past year. These drugs shrink cancer tumors to the size of a pinhead by choking off the blood supply to the tumors. But despite optimistic media attention there have been some major obstacles. The two drugs are so complicated to produce that some researchers have given up on the idea of synthesizing significant amounts in the lab. Angiostatin has not been tried in human trials yet, partly because not enough of it could be made.
A team of scientists led by Duke University researchers in Durham, North Carolina may have found a way to mimic the activity of angiostatin with simpler compounds that are easier to produce. Dr. Sal Pizzo, one of the Duke University researchers, published the findings on March 16, 1999 in the Proceedings of the National Academy of Science.
The potential of angiostatin and endostatin moved into public prominence when a May 3, 1998 New York Times cover story called them a possible revolution in cancer treatment. Newsweek, other national magazines, and numerous television news programs ran features talking about the potential of these new drugs. The publicity made an instant celebrity of Dr. Judah Folkman, the cancer researcher at Children's Hospital in Boston who identified the compounds. But the enthusiasm was tempered when a number of laboratories, including the National Cancer Institute (NCI), had difficulty reproducing Folkman's tumor-shrinking results. In February, the NCI was successful at reproducing the results.
EntreMed, a biotechnology company located in Rockville, Maryland, had the rights to produce angiostatin. However, EntreMed had so many problems producing the compound that its partner, pharmaceutical company Bristol-Myers Squibb, backed out of its investment saying that angiostatin was not a good candidate for human trials.
The Duke team first set out to determine how angiostatin works in mice. The angiostatin drug attaches itself to the cells of blood vessels feeding the tumor. As a result, the tumors are starved and eventually disappear. Malignant tumors can kill normal tissue cells by robbing them of nutrients they need. However, the cells that compose blood vessels that nourish tumors somehow survive. Angiostatin was discovered to kill the blood vessel cells that fed cancerous tumors.
The Duke researchers found that angiostatin apparently works by attaching itself to a protein on the surface of blood vessel cells that scientists did not know existed. The protein is called ATP synthase and is normally seen only inside cells where it makes sure the cells have enough energy to operate. The researchers propose that the ATP synthase protein on the outside of blood vessel cells is what enables them to survive in a tumor, while other cells around them are dying. In theory, angiostatin blocks the protein, preventing the cells from making energy and killing them. Thus a simpler molecule that also binds to the protein could do the same job.
Duke researchers are working hard to find a replacement for angiostatin and have already identified some potential candidates. Current systematic research techniques could allow them to find an angiostatin replacement in a matter of weeks or months.
Updated: January 15, 2009
