The effects of angiostatin and endostatin on mechanisms regulating angiongenesis in other processes besides tumor growth is one area of research that requires additional study, according to noted University of Notre Dame blood chemist Francis J. Castellino.
Basic research conducted in Castellino's laboratory contributed to the identification of angiostatin, one of the promising new cancer drugs being heralded nationally this week. Angiostatin and endostatin are being given top priority by the National Cancer Institute and will be rushed to clinical trial in humans.
Castellino is very excited about the drugs' possibilities but cautions that more studies involving the basic science of these drugs are needed. Research now under way in Castellino's laboratories will attempt to address some of these issues.
Castellino, whose laboratory is without question one of the top handful studying blood clotting mechanisms, is Kleiderer-Pezold professor of biochemistry, dean of Notre Dame's College of Science, and director of the Center for Transgene Research and the Walther Cancer Center, which are also at the University. It was his antibody to plasminogen, a precurser of the clot-dissolving enzyme plasmin -- as well as a number of basic studies on plasminogen fragments -- that helped confirm angiostatin is a fragment of this protein. (Endostatin is derived from a different, unrelated protein, collagen XVIII.)
Angiostatin and endostatin were discovered in the laboratory of Dr. Judah Folkman, a cancer researcher at Children's Hospital in Boston. The drugs function by cutting off the blood supply to tumors, making even extremely large tumors disappear. In mice, the drugs appear to stop malignant tumor growth and spreading, but they have not yet been tested in humans, and the medical community remains cautious.
Both angiostatin and endostatin evidently interfere with the tumors' ability to synthesize new capillaries from pre-existing blood vessels, a process called angiogenesis. Essentially, the tumors were starved when the drugs were administered to cancer-bearing mice.
Normally, only limited angiogenesis takes place in organisms after fetal development. Apart from pathological situations, such as cancer, angiogenesis is needed for events such as embryogenesis, wound repair, and successful skin grafts. "It's important to remember that cancer patients are sick," he explains. "There are other pathologies besides tumors. Many such patients experience difficulties with clotting, bleeding, and vascular damage, for example, and may require some level of neovascularization.
"We have to be careful not to elevate expectations to unreasonable levels prior to the results of clinical trials. However, on the other side, the potential beauty of these drugs is that they may only be required for short-term treatment, and that many of these other issues will be manageable."
A collaborative project between scientists at the Cleveland Clinic, the Notre Dame Center for Transgene Research, and the Walther Cancer Center will study genetically manipulated mice with deletions of angiostatin's parent protein, plasminogen. Results from this in vivo research are expected to yield greater understanding of the angiostatin-plasminogen relationship in cancer, Castellino says.
For more information, contact Frances J. Castellino, Kleiderer-Pezold professor of biochemistry and dean of the College of Science, at (219) 631-6456 or Elliot D. Rosen, research associate professor and associate director of the Transgene Research Center, at (219) 631-9365. Castellino's research is funded by the National Institutes of Health and the American Heart Association. He also has received funding from EntreMed, the Rockland, Md., biotech company that was formed to make and market angiostatin and endostatin, and from the Walther Institute of Indianapolis.
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