NEWS

Anthrax as a Cancer Drug?

F. B. Dunn

Once the home of the U.S. bioweapons program, Fort Detrick, Md., site of a condemned seven-story tower where tons of deadly anthrax spores once lay, now serves as a cynosure of anthrax defense research.



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Fort Detrick in Frederick, Md., is the home of the National Cancer Institute’s Frederick Cancer Research and Development Center and of the U.S. Army Medical Research Institute of Infectious Diseases.

 
In 1969, President Nixon signed an order ending the U.S. bioweapons program. Now, 3 decades later, scientists at Fort Detrick are transforming anthrax’s deadly toxins into 21st century cancer fighters. A mix of basic science and serendipity and a dash of Fort Detrick mythology have brought to light answers to anthrax’s weaknesses and the biowarfare agent’s anticancer potential.

For anthrax infections, current approaches—antibiotics and vaccines—have serious drawbacks. Antibiotics kill anthrax bacteria but do not hinder their lethal toxin. Administer antibiotics a day too late, and—as seen in recent mail attacks—the victim dies. Vaccines, meanwhile, can produce unwanted side effects, and besides, "it’s hard to justify vaccinating a whole country," said Robert Liddington, Ph.D., an anthrax researcher at the Burnham Institute in La Jolla, Calif.

The approaches fostered by Fort Detrick researchers and, now, other groups around the country focus on the weapon instead of its carrier. Anthrax bacteria spit out three proteins that combine at the cell surface. There, they slip inside and wreak their havoc, causing tissue hemorrhaging and, in a week or two, death. Knocking out one of the proteins would knock out anthrax’s kick.

One protein called anthrax lethal factor has garnered much attention. A major step toward neutralizing it came in 1998, when an NCI team led by George Vande Woude, Ph.D., and Nicholas Duesbery, Ph.D., courted serendipity while searching for anticancer agents. As developmental biologists, they had been searching for compounds that inhibit meiosis in frog eggs. One such agent existed but did not work well, said Duesbery, who now works with Vande Woude at the Van Andel Research Institute in Grand Rapids, Mich.

So the team probed NCI’s database of potential anticancer compounds and found a stunning match: anthrax lethal factor. Duesbery contacted Steve Lippla, Ph.D., at the National Institute of Dental and Craniofacial Research, Bethesda, Md., who had urged NCI to add the anthrax proteins to its database for "selfish reasons," to collect some raw data.

Lippla, who spent 1974–1989 at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), also located at Fort Detrick, had engineered nonvirulent strains to produce large amounts of lethal factor and other proteins. He sent some samples of anthrax proteins up to Duesbery.

After "a few months playing with the toxins," Duesbery discovered how lethal factor did its dirty deed: by snapping a vital signaling protein in half, thereby mucking up intracellular communication. Preventing this enzymatic destruction with drugs that block the toxin from breaking the signaling protein is a promising approach, said USAMRIID’s Sina Bavari, Ph.D.

Other approaches look promising as well. A second protein made by anthrax, called protective antigen, sticks to the cell surface, where it pries open a hole. The antigen then grabs two proteins—lethal factor and a third, similar protein—and shuttles them into the cell. Interrupting the process at any of these points would go a long way toward saving patients, said Rekha Panchal, Ph.D., an NCI researcher who collaborates with Bavari.

Three years ago, about the same time Vande Woude and Duesbery published their anthrax findings in Science, Bavari struck on a parallel idea – searching NCI’s database of 60,000 potential anticancer compounds for those that might inhibit anthrax toxin. He proposed a joint venture to his employer, USAMRIID, and three years later the combined team has fingered some promising compounds. But years of work remain between these early leads and a proven drug, he said.

While Fort Detrick buzzes with anthrax activity—scores of technicians at the facility are testing hundreds of samples from government buildings—some of its former workers are busy, too. "The other thing we’ve tried to do is flip it around and look at the antitumor properties of lethal factor," said Duesbery, who left NCI for the Van Andel Institute after feeling "captivated" by the toxin’s properties.

Duesbery and his colleagues broke open this new chain of research earlier this year with a paper in the Proceedings of the National Academy of Sciences that showed lethal factor inhibits tumor cells in vitro and in rodents.

"Lethal toxin did strongly inhibit growth and in some cases even caused a regression of tumors" in nude mice, he said. The toxin stalls melanoma, colon, and breast tumors better than other types, a finding Duesbery and Vande Woude made in 1998.

More recently, Duesbery found an unanticipated antiangiogenic effect. "If you actually looked at the tumors, a normal tumor was purple because it was highly vascularized. But if you looked at one treated with toxin, it was almost a pale yellow." So two anticancer mechanisms appear to be at play—blood vessel inhibition, which limits a tumor’s size, and outright tumor cell destruction.

After the recent wave of scares, it is hard to imagine patients, even the desperate, lining up for anthrax toxin injections. But Duesbery said there are ways to limit its negative effects. If the toxicity can indeed be dealt with, the possibilities are enticing.

Because anthrax toxins preferentially destroy white blood cells called macrophages, "You can use it to your advantage and target proliferative disorders of the lymph," said Duesbery. Another approach, pursued by Leppla, turns the anthrax proteins’ snip-grab-throw action against tumors, by tossing antitumor agents into misfiring cells.

President Nixon vowed to recast Fort Detrick as a "leading center of cancer research," might well appreciate these efforts. But what would he think of an eerie coincidence?

While his directive shuttered most of Anthrax Tower, a low-slung lab wing remained. In 1972, NCI took control of 67 buildings at Fort Detrick, including Anthrax Tower’s laboratories. By 1998, Duesbery had moved in.

When he realized that he had made a discovery that could one day help fell anthrax and cancer in the same building where, as he puts it, "they were making bombs with this stuff," it is easy to imagine him peering up at the boarded tower and shivering at the ghosts.

"Yeah," he said. "It was spooky."



             
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