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Inside "Angiogenesis":
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Angiogenesis as a Drug TargetThe growth of blood vessels into tumors is only half of the story. It was postulated as long ago as 1971 by Dr. Judah Folkman that prevention of angiogenesis could inhibit tumor growth by starving them of vital nutrients.(1) The existence of natural inhibitors of angiogenesis was hinted at by an intriguing observation made by surgeons. They found that the surgical removal of a large primary tumor often led to the rapid development of metastatic growths. This observation suggested that the primary tumor was producing something that kept small metastatic growths from progressing. When the large tumor was removed, the smaller tumors were free to grow. The first naturally occuring inhibitor discovered was thrombospondin, identified in 1989 by Dr. Noel Bouck.(2) Two more natural inhibitors were dicovered by Dr. Michael O'Reilly in Dr. Folkman's lab, angiostatin in 1994 and endostatin in 1997.(3) (4) Both molecules are small proteins that are derived from larger proteins that, remarkably, have different functions in the body. As treatments, the first two inhibitors discovered shared two very exciting features: 1) Because they are natural products of the body, they should be much less toxic than conventional chemotherapy drugs. 2) Because they act on normal (blood vessel) cells instead of attacking the tumors directly, they should be much less likely to lead to the selection of drug-resistant tumors. Angiostatin is no longer being examined as a possible cancer drug. Endostatin, in the form of Endostar® is in clinical trials. Since blood vessel formation, or the lack of it, is at the root of many human diseases, controlling this process has potential in several disorders in addition to cancer. The story of Judah Folkman's search was the subject of a NOVA special that can be viewed online. Since this process is key to the growth of tumors, many drugs are currently being investigated for their potential to inhibit angiogenesis and tumor growth and several drugs with antiangiogenesis activity have been approved to treat cancer. Learn more about angiogenesis inhibitors in the cancer treatment section of the site. A Closer Look at the First Angiogenesis InhibitorsLike all cells, cancer cells require a constant supply of nutrients and oxygen in order to grow and divide. Without an adequate blood supply tumors will not grow. Tumors produce factors that stimulate the formation of blood vessels to provide them with the food and oxygen they need. The process of blood vessel formation is termed angiogenesis.This process is a very active area of research in cancer treatment for several reasons. 1. The treatments should have low toxicity. Angiogenesis occurs at high levels during fetal development, the menstrual cycle and in wound healing. The treatments might be expected to interfere with these processes but should not harm most normal dividing cells. 2.The treatments are not designed to directly attack the cancer cells. The targets of several of these treatments are normal processes controlled by normal cells (such as the cells that form blood vessels), not the tumor cells themselves. The high mutation rates of cancer cells that often render chemotherapy ineffective will not interfere with these drugs. Angiostatin This drug is actually a naturally occuring protein that is derived from the cleavage of a larger protein, plasminogen. Angiostatin inhibits the growth of blood vessels in tumors and has been shown to inhibit metastasis of tumors in animal models. This drug is is no longer in clinical trials(5)(6)(7) Endostatin/Endostar Like angiostatin, this drug is a naturally occuring protein. Endostatin is derived from a form of collagen, a structural protein found in connective tissue. (5)(6) In early trials, endostatin was shown to be safe and exhibit low toxicity. (8)(9)(10)(11) More recently, researchers in China have developed a slightly modified version of endostatin that is more stable, easier to manufacture and more potent(12). The drug still works by inhibiting angiogenesis(13). The new version, Endostar, is currently in clinical trials. Search for current clinical trials involving Endostar. The development and marketing of Endostatin are now being advanced by Alchemgen and Children's Medical Center Corporation
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