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The emergence of bioterrorism has spurred efforts to develop more effective drugs against anthrax. Joanne Chan, PhD, in the Vascular Biology Program at Children's, is finding that existing FDA-approved drugs may counter a serious complication that's largely responsible for anthrax's 85 percent fatality rate.
Within days of exposure, Bacillus anthracis toxins cause fluid to leak out of blood vessels, which, in turn, leads to fluid buildup (edema) in the lungs and severe breathing problems.
Chan hypothesized that anthrax toxins enter blood vessel cells and activate intrinsic mechanisms that make vessels more permeable, or leaky. "If you could regulate permeability at the level of the cell," says Chan, "it might help reduce the vascular permeability that leads to edema and the inability to breathe."
Chan knew that vascular endothelial growth factor (VEGF), a naturally occurring protein that stimulates blood-vessel growth, or angiogenesis, is also involved in permeability. "If vascular permeability is induced by anthrax toxicity, then it might be possible to reduce that by using anti-VEGF agents," Chan explains.
To date, Chan has successfully modeled anthrax toxin-induced permeability in zebrafish and has shown that two small-molecule VEGF inhibitors—similar to ones now used to reduce tumor angiogenesis in end-stage cancer patients—reduce the effects of anthrax toxins.
Exactly how the toxins make vessels leaky is still not fully understood. "We're trying to take one step at a time to analyze all the factors that may be activated through the toxin," says Chan, who is now also testing her ideas in mammalian models of anthrax. She hopes that grant support or collaboration with Army scientists will expedite the research.
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