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New oral angiogenesis inhibitor offers potential nontoxic therapy for a wide range of cancers
July 02, 2008The first oral, broad-spectrum angiogenesis inhibitor, specially formulated through nanotechnology, shows promising anticancer results in mice, report researchers from Children's Hospital Boston. Findings were published online on June 29 by the journal Nature Biotechnology.
Because it is nontoxic and can be taken orally, the drug, called Lodamin, may be useful as a preventive therapy for patients at high risk for cancer or as a chronic maintenance therapy for a variety of cancers, preventing tumors from forming or recurring by blocking the growth of blood vessels to feed them. Lodamin may also be useful in other diseases that involve aberrant blood-vessel growth, such as age-related macular degeneration and arthritis.
Developed by Ofra Benny, PhD, in the Children's laboratory of the late Judah Folkman, MD, Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, MD, PhD, then a fellow in Folkman's lab, and one of the first angiogenesis inhibitors to undergo clinical testing. In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions. Trials were suspended in the 1990s because of neurologic side effects that occasionally occurred at high doses, but it remains one of the broadest-spectrum angiogenesis inhibitors known.
Lodamin appears to retain TNP-470's potency and broad spectrum of activity, but with no detectable neurotoxicity and greatly enhanced oral availability. While a number of angiogenesis inhibitors, such as Avastin, are now commercially available, most target only single angiogenic factors, such as VEGF, and they are approved only for a small number of specific cancers. In contrast, Lodamin prevented capillary growth in response to every angiogenic stimulus tested. Moreover, in mouse models, Lodamin reduced liver metastases, a fatal complication of many cancers for which there is no good treatment.
"The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches," says Ingber, now co-interim director of the Vascular Biology Program at Children's.
TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a postdoctoral fellow in Folkman's lab, who attached a large polymer to prevent it from crossing the blood-brain barrier (Cancer Cell, March 2005). That formulation, Caplostatin, has no neurotoxicity and is being developed for clinical trials. However, it must be given intravenously.
Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470. Experimenting with polymers of different lengths, she found a combination that formed stable, "pom-pom"-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core. The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach's acidic environment, allowing it to be absorbed intact when taken orally. The micelles reach the tumor, react with water and break down, slowly releasing the drug.
Tested in mice, Lodamin had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses. Subsequent tests suggest that Lodamin retains TNP-470's unusually broad spectrum of activity. "I had never expected such a strong effect on these aggressive tumor models," Benny says.
Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival. "This was one of the most surprising things I saw," says Benny. "When I looked at the livers of the mice, the treated group was almost clean. In the control group you couldn't recognize the livers -- they were a mass of tumors."
TNP-470 itself has an interesting history. It was derived from fumagillin, a mold with strong anti-angiogenic effects that Ingber discovered accidentally while culturing endothelial cells (the cells that line blood vessels). Ingber noticed that in certain dishes -- those contaminated with the mold -- the cells changed their shape by rounding, a behavior that inhibits capillary cell growth. Ingber cultured the fungus, disregarding lab policy, which called for contaminated culture to be discarded immediately. He and Folkman later developed TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical Industries in Japan (Nature, December 1990). It has shown activity against dozens of tumor types, though its mechanism of action is only partly known.
"It's been an evolution," says Benny, "from fumagillin to TNP-470 to Caplostatin to Lodamin."
Lodamin and Caplostatin have been optioned for clinical development by SynDevRx, Inc., a Cambridge, Mass.-based biotechnology company. Benny, who is from Israel, coined the name Lodamin from Hebrew. ("Lo dam" means "no blood.") She continues to study Lodamin's effects in other animal models of cancer, and in macular degeneration with Robert D'Amato, MD, PhD, in the Vascular Biology program.
Folkman, the Lodamin paper's senior author, died unexpectedly in January, just days after Benny submitted the paper for publication. The paper, a part of his legacy, is dedicated to his memory.
The study was supported in part by the U.S. Department of Defense.
Children's Hospital Boston
"The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches," says Ingber, now co-interim director of the Vascular Biology Program at Children's.
TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a postdoctoral fellow in Folkman's lab, who attached a large polymer to prevent it from crossing the blood-brain barrier (Cancer Cell, March 2005). That formulation, Caplostatin, has no neurotoxicity and is being developed for clinical trials. However, it must be given intravenously.
Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470. Experimenting with polymers of different lengths, she found a combination that formed stable, "pom-pom"-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core. The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach's acidic environment, allowing it to be absorbed intact when taken orally. The micelles reach the tumor, react with water and break down, slowly releasing the drug.
Tested in mice, Lodamin had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses. Subsequent tests suggest that Lodamin retains TNP-470's unusually broad spectrum of activity. "I had never expected such a strong effect on these aggressive tumor models," Benny says.
Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival. "This was one of the most surprising things I saw," says Benny. "When I looked at the livers of the mice, the treated group was almost clean. In the control group you couldn't recognize the livers -- they were a mass of tumors."
TNP-470 itself has an interesting history. It was derived from fumagillin, a mold with strong anti-angiogenic effects that Ingber discovered accidentally while culturing endothelial cells (the cells that line blood vessels). Ingber noticed that in certain dishes -- those contaminated with the mold -- the cells changed their shape by rounding, a behavior that inhibits capillary cell growth. Ingber cultured the fungus, disregarding lab policy, which called for contaminated culture to be discarded immediately. He and Folkman later developed TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical Industries in Japan (Nature, December 1990). It has shown activity against dozens of tumor types, though its mechanism of action is only partly known.
"It's been an evolution," says Benny, "from fumagillin to TNP-470 to Caplostatin to Lodamin."
Lodamin and Caplostatin have been optioned for clinical development by SynDevRx, Inc., a Cambridge, Mass.-based biotechnology company. Benny, who is from Israel, coined the name Lodamin from Hebrew. ("Lo dam" means "no blood.") She continues to study Lodamin's effects in other animal models of cancer, and in macular degeneration with Robert D'Amato, MD, PhD, in the Vascular Biology program.
Folkman, the Lodamin paper's senior author, died unexpectedly in January, just days after Benny submitted the paper for publication. The paper, a part of his legacy, is dedicated to his memory.
The study was supported in part by the U.S. Department of Defense.
Children's Hospital Boston
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Angiogenesis: An Integrative Approach from Science to Medicine by William D. Figg (Author), William D. Figg (Editor), Judah Folkman (Editor) Dr. Judah Folkman, father of angiogenesis , (1933-2008) was the Director of the Vascular Biology Program, Andrus Professor of Pediatric Surgery, and Professor of Cell Biology at Harvard University's Boston Children's Hospital. In the 1971 issue of The New England Journal of Medicine, he proposed the theory that tumor growth is angiogenesis dependent. This premise was the basis of this field of research and has become the focus of scientists worldwide. Because of Folkman's discovery and research, the possibilities of antiangiogenic and angiogenic therapy have broadened beyond cancer to many noncancerous diseases. This book represents the first collection in a volume of which Dr. Folkman is co-editor. Dr. Folkman authored nearly 400 original papers and more than 100 book... |
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Angiogenesis: In Vivo Systems, Part A, Volume 444 by Academic Press Angiogenesis is the growth of new blood vessels and is an important natural process in the body. A healthy body maintains a perfect balance of angiogenesis modulators. In many serious disease states, however, the body loses control over angiogenesis. Diseases that are angiogenesis-dependent result when blood vessels either grow excessively or insufficiently. Understanding how angiogenesis "works" and how to control it, will have massive implications on the management, treatments, and ultimately the prevention of many common (and not so common) diseases. Angiogenesis cuts across virtually every discipline. The Angiogenesis Foundation identified angiogenesis as a "common denominator" in our most serious diseases. Excessive angiogenesis occurs in diseases such as cancer, diabetic... |
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Angiogenesis Protocols (Methods in Molecular Biology) by Stewart Martin (Editor), Cliff Murray (Editor) As experimentation and clinical trials with first generation anti-angiogenic agents have yielded results and our understanding of the biology and physiology of blood and lymphatic vessels has increased, a new angiogenesis volume swiftly became a necessity. "Angiogenesis Protocols, Second Edition" remains true to its original vision of providing a single source for angiogenesis researchers, irrespective of levels of resource and expertise, by collecting a range of methods for cell isolation and assessing angiogenesis in vivo or in vitro. This information, however, is expanded to include chapters on circulating endothelial progenitor cells, angiogenic signalling pathways, imaging of angiogenesis, and measurement of tissue blood flow.Written in the "Methods in Molecular Biology" series... |
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Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer by Random House In 1961, twenty-eight-year-old Dr. Judah Folkman saw something while doing medical research in a United States navy lab that gave him the first glimmering of a wild, inspired hunch. What if cancerous tumors, in order to expand, needed to trigger the growth of new blood vessels to feed themselves? And if that was true, what if a way could be found to stop that growth? Could cancers be starved to death? Dr. Folkman had ample reason to be self confident — second in his class at Harvard Medical School, he was already considered one of the most promising doctors of his generation. But even he never guessed that his idea would eventually grow into a multibillion-dollar industry that is now racing through human trials with drugs that show unparalleled promise of being able to control... |
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Angiostop 250 mg - 60 capsules | Slows Angiogenesis by Chi's Enterprise Angiostop is extracted from a special sea cucumber in the South China seas. Its active fraction has been shown through in vitro and in vivo studies to inhibit angiogenesis (new blood vessel formation) and also inhibit receptor tyrosine kinases (RTKs). Studies show that the active fraction inhibits 4 different angiogenesis-related RTKs. By stopping the cytokines from binding to their corresponding RTKs, factors such as angiogenesis and proliferation are inhibited and apoptosis (programmed cell death) is induced. * Inhibits 4 receptor tyrosine kinases (RTKs):VEGFR, FGFR, PDGR, EGFR * Inhibits new blood vessel formation * Induces apoptosis Inhibiting the vascular endothelial growth factor receptor (VEGFR) is the most important because it stops angiogenesis, cutting off nutrient and... |
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Angioblock ( Supports the body in inhibiting angiogenesis ) 1000 mg 120 Capsules Nutricology by Nutricology AngioBlock is a water extraction of the leaves of the herb Convolvulus arvensis, commonly known as bindweed, and is rich in proteoglycan mixture (PGM). In combination with proper nutrition, it enhances the Defense mechanism of body's ability to maintain good health. The bindweed contained in VascuStatin Formula is grown in Wyoming, and the toxic alkaloids are removed by a proprietary process. |
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Angiogenesis: From Basic Science to Clinical Applications by Napoleone Ferrara (Editor) Integrating the latest advances in basic science, this book reviews the status of the clinical applications of angiogenic growth factors and inhibitors. Angiogenesis: From Basic Science to Clinical Applications explores current molecular and genetic findings on the regulation of angiogenesis, discusses the results of clinical trials and identifies the pathological conditions that are most likely to benefit from such treatments. Edited by a foremost researcher in the field, the book includes contributions from experts in a variety of disciplines, supplemented by illustrations and photographs. This unique combination of information offers a truly a state-of-the-art review of the science. |
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Angiogenesis: In Vitro Systems, Volume 443 (Methods in Enzymology) by Academic Press Angiogenesis is the growth of new blood vessels and is an important natural process in the body. A healthy body maintains a perfect balance of angiogenesis modulators. In many serious disease states, however, the body loses control over antiogenesis. Diseases that are angiogensis-dependent result when blood vessels either grow excessively or insufficiently. * Tried-and-tested techniques written by researchers that developed them, used them, and brought them to fruition * Provides the "builder's manual" for essential techniques--a one-stop shop that eliminates needless searching among untested techniques * Includes step-by-step methods for understanding the cell and molecular basis of wound healing, vascular integrin signaling, mechanical signaling in blood vessels,... |
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Tumor Angiogenesis: Basic Mechanisms and Cancer Therapy by Dieter Marmé (Author), Dieter Marmé (Editor), Norbert Fusenig (Editor) Tumor angiogenesis is one of the most prominent mechanisms driving tumor development and progression. In the past 30 years some of the most important signaling pathways linking specific angiogenic activities of tumor cells to fatal reactions of the patient s vascular system have been elucidated. Crucial targets for therapeutic intervention have been identified and validated. Based on these achievements targeted drug development programs have been implemented to interfere with tumor angiogenesis as an attractive strategy in cancer treatment. The first targeted anti-angiogenic drugs have been approved for a variety of solid metastasizing cancers. Part 1 describes the basic mechanisms. Tumor-angiogenic signaling pathways are presented as new potential targets for... |
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Angiogenesis: In Vivo Systems, Part B, Volume 445 by Academic Press Understanding how angiogenesis "works" and how to control it will have massive implications on the management, treatments, and ultimately the prevention of many common (and not so common) diseases. Angiogenesis is the growth of new blood vessels and is an important natural process in the body. A healthy body maintains a perfect balance of angiogenesis modulators. In many serious disease states, however, the body loses control over angiogenesis. Diseases that are angiogenesis-dependent result when blood vessels either grow excessively or insufficiently. * Tried-and-tested techniques written by researchers that developed them, used them, and brought them to fruition * Provides the "builder's manual" for essential techniques--a one-stop shop that eliminates needless searching... |
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