A new study by cardiologists and researchers at UCSF found that high concentrations of cocoa flavanols—natural compounds found in apples, grapes, tea, cocoa and cherries—decrease blood pressure and improve the health of blood vessels in patients with heart disease. The UCSF team showed for the first time that increasing angiogenesis-promoting cells in the blood is one of the possible mechanisms of flavanol's heart benefit. Findings are published in the July 13, 2010 issue of the Journal of the American College of Cardiology.

The study included 16 coronary artery disease patients aged 64 (± 3 years) who were given a high-flavanol cocoa drink (375 mg of flavanols) twice a day over 30 days, and then a nutrient-matched low-flavanol cocoa drink (9 mg flavanols) twice a day over 30 days. The participants continued taking all regular medications for their underlying heart disease during the study, including cholesterol-lowering medications. ... Read More

Research conducted at the Washington University School of Medicine in St. Louis indicates that resveratrol, a naturally occurring compound found in red wine, grapes, blueberries, peanuts, and other plants, inhibits the abnormal growth of new blood vessels, or angiogenesis, in the eye. The discovery has implications for preserving vision in devastating blinding diseases, such as diabetic retinopathy and age-related macular degeneration (AMD), the leading cause of blindness in Americans over age 50.

Prior studies have shown that resveratrol’s anti-aging and cancer preventative effects are the function of specific proteins, known as sirtuin family proteins. Surprisingly, in the Washington University study, resveratrol inhibited angiogenesis via a novel, sirtuin-independent pathway, known as a eukaryotic elongation factor-2 kinase (eEF2) regulated pathway. This finding suggests that blocking eEF2 is a putative therapeutic strategy to treat a number of angiogenesis-dependent diseases. The related report appears in the July 2010 issue of The American Journal of Pathology. ... Read More

The U.S. Food and Drug Administration (FDA) has approved Lucentis (ranibizumab injection) for the treatment of a condition called macular edema that occurs after another blinding condition known as retinal vein occlusion (RVO). RVO is a leading cause of blindness in elderly people. The FDA approval comes after review of the results from two major clinical trials showing significant improvement in vision in patients with RVO who receiving Lucentis.  People treated with monthly Lucentis injections showed sustained vision improvement during the 6-month study. The beneficial effects were seen as early 1 week after start of treatment in some patients.

The two studies, called BRAVO and CRUISE compared changes in best-corrected visual acuity (BCVA)—a key vision indicator—at 6 months in patients who received Lucentis or sham injections (placebo). In the BRAVO study, 61% of patients in the Lucentis arm gained 15 or more letters in BCVA at 6 months, compared with 29% in the placebo arm. In the CRUISE study, 48% and 17% of patients experienced improvement in the Lucentis and placebo arms, respectively. No new safety events were observed in either study.... Read More

A research team from McGill University in Montreal, Canada, reported that heart function in mice was preserved when monocytes—a type of infection-fighting white blood cell produced in the bone marrow—were implanted following a heart attack. Monocytes also stimulate the growth of new blood vessels, or angiogenesis.

Angiogenesis is important for the repair of damaged heart tissue. The researchers therefore chose to grow monocytes derived from mouse blood under angiogenic conditions prior to transplantation, in order to determine if these so-called monocyte derivatives (MDs) could be beneficial. They found that when MDs were transplanted into animal models of myocardial infarction, simulating a heart attack, the MDs secreted high levels of a variety of beneficial growth factors that have anti-inflammatory properties and that stimulated the growth of endothelial cells that comprise the inner lining of blood vessels.... Read More

The venom of the European honeybee is used for treating various diseases in Oriental medicine. In a recent paper published in the online journal Cancer Letters, Korean researchers investigated the potency of bee venom as an inhibitor of new blood vessel growth (angiogenesis) in lung cancer. Angiogenesis is a critical process in the development and spread of most cancer types.

First, using a standard angiogenesis assay called Matrigel, the researchers were able to show that bee venom does, in fact, inhibit angiogenesis. The venom reduced the production by lung cancer cells of a key protein that stimulates angiogenesis, called vascular endothelial growth factor (VEGF).  Bee venom also diminished the activity of the proteins primary cellular receptor, VEGFR-2, which also controls angiogenesis.... Read More

A blood vessel-blocking drug called tasquinimod slowed the rate of disease progression in a clinical trial of 200 prostate cancer patients, according to experts at Johns Hopkins, Roswell Park Cancer Institute, and Duke University. Tasquinimod is an "anti-angiogenesis" drug that cuts off the blood supply to prostate cancers by blocking new blood vessel development. Like all tumors, prostate cancer requires these networks of blood vessels to supply oxygen and nutrients required for growth.

The multicenter trial of tasquinimod took place at seven institutions, including Johns Hopkins School of Medicine, and enrolled prostate cancer patients whose disease had spread.  The patients took a once-daily pill for 4 weeks. At 6 months, 57 percent of men who received tasquinimod had no disease progression, compared to the 33 percent taking a placebo. Overall, the drug added approximately 12 weeks of time that the disease did not worsen, an endpoint known as progression-free survival.... Read More

An important breakthrough for the treatment of ovarian cancer has been announced.  A Phase III clinical trial has shown that adding the antiangiogenic agent bevacizumab (Avastin) to standard chemotherapy, and then continuing treatment with a maintenance dose of Avastin, can significantly extend the time women with previously untreated advanced ovarian cancer live without their disease getting worse. Women who received the new combined treatment regimen had no worsening of their disease for 14.1 months, compared to 10.3 months for women who got standard therapy—this translates to a 28% reduction in the risk of cancer progression.

Continuing the Avastin as maintenance therapy appears to be important, since women who received Avastin plus chemotherapy but did not receive the maintenance Avastin did not experience a greater survival advantage. The results of this clinical trial were presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 4-8 in Chicago.... Read More

Cancer drugs that inhibit tumor blood vessel growth, called angiogenesis inhibitors, can be used effectively while minimizing elevated blood pressure (hypertensive) side effects if patients' blood pressure is closely monitored and controlled, a clinical panel has determined. The Cardiovascular Toxicities panel, convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee drafted new recommendations for oncologists using antiangiogenic agents for the treatment of cancer. Hypertension, associated with the targeting of an angiogenic protein called VEGF (vascular endothelial growth factor) is the most common side effect of this class of cancer drugs.
Assessing and treating any pre-existing hypertension using standard medications before starting angiogenesis inhibitors, and then closely monitoring patients’ blood pressure in the days after beginning treatment can help physicians control this side effect, the panel concluded in their report, published in the Journal of the National Cancer Institute (2010;102(9):596-604). "This paper should impact practice today," said Michael Maitland, M.D., Ph.D., assistant professor of medicine at the University of Chicago Medical Center and lead author on the commentary. "It should make things safer on average for patients, and will give physicians important guidance."
The panel recommended that patients should be thoroughly screened before treatment with angiogenesis inhibitors, and a risk assessment performed, similar to the cardiovascular assessment patients receive before major surgery, Dr. Maitland said. Before treatment begins, blood pressure in high-risk patients should be reduced and maintained at less than 140/90 mmHg, or even lower in patients with diabetes or chronic kidney disease.... Read More

Curcumin, a dietary polyphenol derived from the root of the plant Curcuma longa, has shown potential as a chemopreventive (cancer-preventing) substance, with beneficial effects affecting different stages of cancer development. Curcumin has an anti-tumor effect by modulating the multiple genes involved in tumor cell proliferation, programmed cell death, invasion, and new blood vessel growth (angiogenesis). The poor absorption of orally ingested curcumin, however, has been considered a limitation of its use in cancer prevention.

Researchers at Wayne State University, Detroit, and the University of Minneapolis, have now developed an injectable, sustained-release formulation of curcumin microparticles that dramatically inhibited the growth of tumors in laboratory mice. The microparticles, consisting of microscopic spheres of curcumin in a biodegradable polymer, were injected into mice bearing human breast cancer tumors. Mice that received the curcumin microparticles had significantly less tumor growth and a reduction in markers of tumor angiogenesis, including the development of microscopic tumor capillaries and expression of a key angiogenic protein, compared with mice that received a placebo. ... Read More

Brain metastases are a major cause of death in patients with advanced lung cancer. Avastin, a drug that interferes with the growth of tumor blood vessels (angiogenesis), is approved to treat both advanced non-small cell lung cancer (NSCLC) and a type of primary malignant brain tumor called glioblastoma. To date, however, there has been little information about the use of Avastin in lung cancer patients with brain metastases. Furthermore, the drug has typically been withheld from these patients due to concerns about bleeding risk.
 
In a small study published online in the Journal of Neuro-oncology, researchers at Sloan Kettering Cancer Center in New York identified 6 lung cancer patients who had received Avastin for treatment of active brain metastases—5 patients had experienced progressive metastases despite prior treatment for lung cancer, and one patient had received no prior treatment. Avastin was administered alone or combination with various chemotherapy drugs. ... Read More

Numerous scientific studies have shown the cancer protective effects of increasing intake of cruciferous vegetables, including broccoli, cauliflower, Brussels sprouts, kale and cabbage. Among the beneficial chemical components of these vegetables is sulforaphane, a naturally occurring compound that suppresses both cancer cell growth and the growth of new tumor blood vessels (angiogenesis). The antiangiogenic properties of sulforaphane have been studied, and it downregulates the production by cancer cells of key angiogenesis-promoting factors, including vascular endothelial growth factor (VEGF), HIF-1α, matrix metalloproteinase-2 and matrix metalloproteinase-9.

Using an extract of sulforaphane, a group of researchers led by Yanyan Li and Duxin Sun at the Department of Pharmaceutical Sciences, University of Michigan, were able to inhibit the growth of breast cancer stem cells both in laboratory cultures and in mice. A growing body of research indicates that many types of cancer, including breast cancer, are initiated and maintained by a small fraction of tumor stem cells—characteristics that make them an attractive target for therapy.... Read More

 Glucocorticoids are a class of steroids used to treat a wide array of chronic medical conditions, such as asthma, ulcerative colitis, and a number of rheumatologic disorders. Long-term use of glucocorticoids, however, causes bone loss and eventually can result in severe osteoporosis and fractures, as well as osteonecrosis (bone death). Osteonecrosis of the hip joint contributes to approximately 10% of the 500,000 hip replacements annually in the US. In addition, long-term steroid therapy significantly increases the risk of hip fractures. Currently, surgery is the only treatment option for this condition.

Now, researchers at Mount Sinai School of Medicine have found a potential new treatment for steroid-induced osteonecrosis of the hip, one that works by stimulating new blood vessel growth (angiogenesis) at the femoral head—the part of the hip joint most vulnerable to osteonecrosis from steroid therapy. The research is published in the April 27 issue of Proceedings of the National Academy of Sciences.... Read More

Statins are cholesterol-lowering medications used by millions of people to lower their risk of heart disease and associated mortality. There has been growing interest in the potential anticancer activity of statins, based on preclinical studies showing that these drugs inhibit cancer cell proliferation and angiogenesis (new blood vessel growth), and that they may sensitize some types of cancerous tumors to radiation therapy.

A new study conducted by researchers at the University of Chicago and published in the Journal of Clinical Oncology sought to determine whether statin use is associated with improved clinical outcomes in patients treated with radiotherapy (RT) for prostate cancer. In total, 691 men with non-metastatic prostate adenocarcinoma treated with RT with the intent to cure the disease, between 1988 and 2006, were included in the retrospective analysis. Of those, 189 patients (27%) were using statins, either during initial consultation or during follow-up examinations. Lipid panels to measure blood cholesterol levels were collected in 298 patients with a median of 5 months before the initiation of RT. Median follow-up was 50 months after RT.... Read More

A form of specialized muscle cells surrounding capillaries, called a pericyte, has been discovered to play a role in initiating angiogenesis, or blood vessel growth, according to researchers at Tufts University School of Medicine (TUSM) and the Massachusetts Institute of Technology (MIT). The study, published in Journal of Physics: Condensed Matter, suggests that these cells use mechanical forces to initiate "sprouting" of new blood vessels, a new discovery in the angiogenesis field. 

Previously, scientists have focused on the chemical signals that initiate angiogenesis and have developed drugs, known as angiogenesis inhibitors, to impede these signals in cancerous tumors and in blinding diseases, such as age-related macular degeneration. Now, it appears that the mechanical signals from pericytes can also play a role in regulating angiogenesis.... Read More

Patients undergoing radiation therapy for cancers of the central nervous system (CNS) or head and neck are at risk for a serious long-term side effect called radiation necrosis. This complication usually appears between a few months to more than a year after radiation treatment, and can be accompanied by a host of neurological symptoms, including impaired memory and thinking ability, personality changes, and vision disturbances, among others. Patients with radiation necrosis may be treated with steroids to reducing brain swelling, blood thinners to improve blood flow in the brain, or other more experimental treatments.

A new study conducted by researchers at the University of Texas M.D. Anderson Cancer Center in Houston suggests that the antiangiogenic therapy Avastin may be a useful new treatment for radiation necrosis. Fourteen patients with documented radiation necrosis were entered into a placebo-controlled, double-blind study of Avastin administered at 3-week intervals. Results showed that all of the patients who received Avastin had improvements in necrosis visible on magnetic resonance imaging (MRI), and all had improvement in their neurological symptoms. None of the patients who received placebo had any improvement. In patients who received all 4 study doses of Avastin, only 2 had any recurrence of necrosis on MRI; 1 patient received an additional Avastin dose, and the other, two additional doses.... Read More

Kidney cancer patients often face difficult surgeries to remove or reduce the size of cancerous tumors, called nephron-sparing surgery (NSS). These patients often receive chemotherapy in an effort to shrink the tumor prior to NSS—called neoadjuvant therapy. Results from a new study published in the British Journal of Urology International show that the angiogenesis inhibitor Sutent, which is approved to treat metastatic kidney cancer, reduces tumor size in kidney cancer patients prior to NSS.

In the study, which was conducted at the University of California San Diego School of Medicine, 12 patients (7 men and 5 women; average age 60 years) received two 28-day cycles of Sutent prior to NSS.  All patients had a reduction in tumor size during treatment, with the average tumor shrinking by 21%, and all patients were able to undergo NSS. At an average follow-up of 2 years, 10 of the 12 patients were alive, 1 patient died from metastatic kidney cancer, and none of the patients required dialysis. Because kidney cancer is so difficult to treat once it spreads beyond the kidney, surgery to remove the tumor usually represents the best hope to control the disease. A new drug that could improve the success of NSS would therefore be an important step forward in the treatment of kidney cancer.

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New research published in the online journal BMC Cancer indicates that a common anti-parasite medication suppresses two key growth factors involved in new blood vessel growth (angiogenesis) in cancerous tumors. The drug, albendazole, marketed as Albenza, Eskazole, Zentel and Andazol, is used to treat a variety of worm infestations, including human and animal tapeworms and roundworms.

Researchers at the National Cancer Institute in collaboration with the University of New South Wales, Australia, found that mice with ovarian tumors treated with albendazole had significant reductions in vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF-1). VEGF and HIF-1 play key roles in initiating and maintaining tumor angiogenesis across many cancer types, and are thus attractive targets for antiangiogenic therapy. HIF-1 in particular is thought to be involved in tumor invasion and spread to distant organs. ... Read More

In people who have suffered a stroke, blood flow must be restored to affected areas of the brain in order to minimize long-term effects, and death. Studies have shown that the infusion of a type of stem cell called mesenchymal stem cells (MSCs), derived from the bone marrow, can improve the motor function of laboratory rates following an experimental stroke. MSCs have the potential to develop, or differentiate, into many different types of connective tissue, and new research indicates that new blood vessel growth (angiogenesis) is largely responsible for the improvements seen with MSC therapy.

Researchers at Sapporo Medical University, Japan, and at Yale University Medical Center, New Haven and the VA Medical Center, West Haven, Connecticut, intravenously infused MSCs into rats at different time points following strokes to determine if the cells could promote new capillary growth in the brain and improve function. They found that rats that received MSCs up to 1 month after a stroke had greater angiogenesis near the borders of the damaged areas of the brain and performed better on a treadmill test than did rats that did not receive the treatment. This striking results suggests that the time window for treating stroke using MSC therapy may be as long as a month after the stroke occurs, although only rats treated earlier (7 days after stroke) had actual reductions in the size of the stroke lesion.  Conventional thinking is that treatment for stroke must occur within the first 12-24 hours after the event.... Read More

A drug commonly used to treat fungal infections has been found to have antiangiogenic properties, which could make it a good candidate for a cancer therapy. Researchers at Stanford University found that itraconazole (Sporanox), an agent used mainly to treat infections caused by the fungus Aspergillus, blocks an important cancer signaling pathway called Hedgehog. Mice treated with an oral formulation of the drug had significantly slower growth of skin tumors than untreated mice. Hedgehog is a cellular pathway involved in tumor growth and angiogenesis, the growth of new blood vessels. Inhibition of angiogenesis by targeting Hedgehog is being pursued by several biotechnology to create new cancer drugs.

An earlier study conducted by researchers at Johns Hopkins University found that itraconazole inhibits the proliferation of endothelial cells—cells the line the inner wall of blood vessels, and also blocks two critical pro-angiogenic proteins called vascular endothelial growth factor and basic fibroblast growth factor. Cancerous tumors produce high amounts of these and other pro-angiogenic growth factors in order to develop a blood supply. Therefore itraconazole may interfere with tumor angiogenesis through this mechanism. They also found that itraconazole inhibits another substance involved in angiogenesis—lanosterol 14alpha-demethylase (14DM). Taken together, these findings suggest that itraconazole has the potential to serve as an antiangiogenic drug, and that lanosterol 14DM may be a promising new target for developing new angiogenesis inhibitors.... Read More

Immune messenger chemicals in the body regulate the immune response by stimulating the production of growth factors or other chemical messengers to initiate or terminate an immune reaction. Interferons are used to treat several forms of cancer, although exactly how the drugs work has not been previously clear. Now, German scientists have found that a natural molecule present in the immune system called beta-interferon inhibits cancerous tumors’ attempts to connect to the blood circulatory system.  Beta-interferon hinders the production of growth factors that support the formation of new blood vessels.

Researchers from the Helmholtz Center for Infection Research (HZI) in Braunschweig, Germany grew skin tumors in two groups of mice. Mice in the first group were not able to produce beta-interferon, while mice in the second group produced the immune substance in normal amounts. The researchers found that the tumors in the mice that could not produce interferon grew considerably larger and had more metastases.... Read More

Researchers at the University of Texas at Austin have uncovered genes in yeast cells that humans may someday use to grow needed blood vessels.  Even though yeasts lack any blood vessels, they use the same genes involved with blood vessels to repair their cell walls in response to stress. These genes could become targets for drugs that block blood vessel growth to tumors and other diseases, including arthritis, diabetic blindness, age-related macular degeneration, psoriasis, and even potentially Alzheimer's disease.

Edward Marcotte, professor of chemistry and biochemistry, and his graduate students developed a computer algorithm that first sifts through vast sets of existing genomic data representing the genes of worms, mice, yeast, plants and humans. The algorithm pairs up sets of genes that overlap between these organisms and humans. In doing so, it identifies and highlights genes that are known to work together for a specific purpose in the non-human organisms, but the functions of which are not yet known in humans. The scientists can then test those new genes in the lab to determine their function.... Read More

William W. Li, M.D. and Vincent W. Li. M.D., M.B.A of the Angiogenesis Foundation will give presentations at the Symposium for Advanced Wound Care (SAWC) on Tuesday, April 20, at the Gaylord Palms Convention Center, in Kissimmee, Florida. Addressing leading physicians, nurses, physical therapists, researchers, podiatrists, dietitians, and other health professionals involved in wound healing or wound care issues, they will share insights from the angiogenesis field to help improve wound care.

Many commonly used methods used by clinicians to aid the healing process, such as growth factors, hyperbaric oxygen, tissue engineered skin, and negative pressure therapy, all promote angiogenesis, new blood vessel growth, that is vital to successful healing. Dr. William Li and Dr. Vincent Li will discuss these approaches.  Similarly, there exists many medications and therapies for other ailments that can inhibit angiogenesis, especially for treating cancer.  As cancer patients live longer and more productive lives with targeted antiangiogenic therapies, the potential that their treatments may slow or delay healing process should be monitored by clinicians, especially in patients who are more vulnerable to non-healing wounds, such as those with diabetes. Dr. Li will present the evidence supporting this recommendation.  Other key data that will be discussed by the Angiogenesis Foundation include updated information on the boxed warning for the drug becaplermin (Regranex).... Read More

Cinnamon, the dry bark and twig of Cinnamomum spp., is one of the world’s most popular and oldest spices. Cinnamon extract has been found to possess potent antioxidant, antimicrobial, and antipyretic (fever reducing) properties. Several recent studies have found that cinnamon extract also has anticancer activity. Cinnamon extract was shown to inhibit blood cancer cell proliferation in laboratory experiments and melanoma tumor growth in mice. New research now shows that cinnamon extract also inhibits vascular endothelial growth factor (VEGF), a potent angiogenesis-stimulating protein.

As a critical factor in tumor angiogenesis—the process by which cancerous tumors develop their own blood supply—VEGF is a primary target for antiangiogenic cancer treatment. The identification of naturally occurring VEGF inhibitors derived from diet offers a potential approach for cancer prevention. Using laboratory tests, scientists associated with the US Department of Agriculture and the Beckman Research Institute found cinnamon extract to be a potent inhibitor of the primary receptor for VEGF, VEGF receptor-2, on endothelial cells—the cells that line the inner walls of blood vessels and that are activated during tumor angiogenesis. In cell cultures and in mice, cinnamon extract inhibited VEGF-induced endothelial cell proliferation and the formation of tumor blood vessels. ... Read More

Researchers at Uppsala University, in collaboration with colleagues in Sweden, Norway, Finland, and Germany, have identified an entirely new mechanism by which the body inhibits the formation of abnormal new blood vessels. The discovery could lead to new treatments for cancer and other diseases that are dependent upon angiogenesis. Already, there a number of approved antiangiogenic drugs that have dramatically improved the treatment outlook for some patients with several common and deadly cancer types.

The new study investigated the function of a protein called histidine-rich glycoprotein (HRG) that is naturally is present in blood plasma circulating throughout the body. Previous studies in mice have shown that HRG inhibits angiogenesis and tumor growth. The new study demonstrated, among other things, that the HRG fragment responsible for the inhibitory effect is present in human tissue, which suggests that it is part of the body's own defense system against abnormal angiogenesis, as may occur in cancer.... Read More

Researchers at Johns Hopkins have developed a new technique for delivering adult stem cells into the legs of patients to treat peripheral arterial disease, or PAD, a condition of poor circulation in the legs that affects about 10 million Americans. Left untreated, PAD progresses to serious complications, including chronic wounds, gangrene, limb loss, and even death.

The researchers used a technique that encapsulates bone marrow stem cells in “microbubbles” derived from seaweed. The stem cells, which can either be harvested from the patient’s own bone marrow or supplied by a donor, create natural proteins known as growth factors that promote the formation of new vessels, or angiogenesis. ... Read More

For several years, researchers have been working on a new approach to treating cancer, using viruses to infect and kill cancer cells while leaving normal cells unharmed. This approach, called oncolytic virotherapy, has the potential advantage of having low toxicity compared to traditional cancer chemotherapy treatments. Now, researchers at the Mayo Clinic in Rochester, Minnesota, have combined oncolytic virotherapy with antiangiogenic cancer therapies that attack the tumor blood supply to induce substantial regression of tumors in laboratory mice.

Cancerous tumors recruit their own supply of new capillary blood vessels (angiogenesis) in order to grow and spread. One of the critical proteins that promote tumor blood vessel growth, vascular endothelial growth factor (VEGF), is the primary target of drugs used to treat several types of cancer. VEGF stimulates the proliferation of endothelial cells—the cells that line the inner walls of blood vessels. Malignant tumors secrete high levels of VEGF to facilitate the growth of blood vessels that feed the tumor with oxygen and nutrients.... Read More

A new report by British physicians published online in the journal Retinal Cases & Brief Reports used the antiangiogenic drug Avastin® (bevacizumab) to treat Sorsby Fundus Dystrophy (SFD), a genetic, early onset form of macular degeneration. It is apparently the first time Avastin has been used to treat the rare genetic condition, which causes a build-up of leaky blood vessels behind the retina, resulting in vision loss.

Two patients with SFD, both in their 30s, were treated with injections of Avastin, which resulted in resolution of abnormal blood vessel growth and significantly improved vision in the treated eyes. Avastin, best known as a cancer therapy that blocks the growth of tumor blood vessels, is also used to treat "wet" age related macular degeneration (AMD), the leading cause of blindness in the western world in people over age 50. ... Read More

New research published in the Journal of Clinical Investigation indicates that antiangiogenic drugs designed to fight cancer by blocking tumor blood supply could also augment treatment for a wide range of infectious diseases by boosting the body’s immune response.

Researchers at the Centre for Immunology and Infection at the University of York, United Kingdom, show that antiangiogenic drugs administered with antimicrobial therapy can reverse damage to certain immunity-generating organs and tissues, such as the spleen. These organs and tissues are often destroyed by chronic infection or inflammation. Their research focused on a tropical disease called visceral leishmaniasis that is caused by a single-celled parasite. Each year, there are approximately 2 million cases of leishmaniasis worldwide, of which 500,000 are of the potentially fatal form of the disease (visceral leishmaniasis). ... Read More

Elevated increased blood pressure (hypertension) is a common, treatable side effect of antiangiogenic cancer therapies. Now, new study findings in more than 500 patients indicate that development of hypertension may predict therapy response in patients with advanced kidney cancer treated with the antiangiogenic drug Sutent® (sunitinib). Sutent is one of a number of approved cancer agents that block tumor blood vessel growth, and is approved to treat advanced kidney cancer, or renal cell carcinoma (RCC).

Researchers examined data from three clinical trials of Sutent in 544 patients with metastatic RCC. Hypertension in the analysis was defined as a maximum average systolic blood pressure (SBP) ≥ 140 mmHg and a maximum average diastolic blood pressure (DBP) ≥ 90 mmHg. ... Read More

Squid ink is used as a defense mechanism in many species of marine cephalopods, and is also considered a delicacy in Spanish and other cuisines.  It now joins a growing number of marine-derived sources of naturally occurring inhibitors of angiogenesis.

A new paper in the journal Carbohydrate Polymers illuminates the potential anti-cancer properties of a sulfated polysaccharide isolated from the ink of the squid Ommastrephes bartrami. Ommastrephes bartrami, known as the neon flying squid, is a species found in the western Pacific Ocean. In laboratory experiments, squid ink polysaccharides (SIPs) inhibited angiogenesis, the growth of new capillary blood vessels, and the invasion and migration of tumor cells. Angiogenesis is critical for the growth and development of cancerous tumors. This is the first study to show that substances derived from squid ink could form the basis of new therapies for the prevention of tumor metastasis and possibly angiogenesis.... Read More

Cancer patients with brain metastases have until recently been excluded from clinical trials of the antiangiogenic drug Avastin® (bevacizumab) due to concerns about a possible risk of bleeding in the brain. Results from a major new analysis involving thousands of cancer patients, however, indicate that Avastin does not increase the risk for intracranial bleeding in patients with brain metastases.

Researchers examined safety data from 8,443 patients in 13 randomized clinical trials, two open-label safety trials, and two more recent prospective trials. In the 13 randomized studies, previously undiagnosed brain metastases were identified in 187 patients (91 in Avastin-treated patients, and 96 in patients not treated with Avastin). Among them, 3 Avastin-treated patients (3.3%) developed serious bleeding in the brain, whereas 1 non Avastin-treated patient (1.0%) developed a fatal cerebral hemorrhage.... Read More

Dr. William W. Li, M.D., president and medical director of The Angiogenesis Foundation, will address an international convention of clinical and research leaders in the field of diabetic foot treatment to discuss the latest approaches in the treatment of diabetic foot conditions at the Diabetic Foot Conference (DFCON) in Los Angeles.  Dr. Li will address the convention, offering insight into how angiogenesis can successfully address the problem of slowly healing diabetic foot wounds.  

DFCON is a international convergence of leading doctors, clinicians and researchers, dedicated to the treatment of diabetic foot conditions and amputation prevention. A debilitating side effect of the disease, diabetic patients have an impaired ability to heal wounds due to sensory nerve problems and difficulties growing new blood vessels (angiogenesis) during this healing process, which can often lead to amputation of the foot or larger portion of the lower leg.

Since 1997, The Angiogenesis Foundation has been actively involved with advancing the treatment of diabetic foot conditions through new modalities that actively promote angiogenesis. The Foundation is also promoting a new regenerative medicine approach using gene and cell therapies to boost the body's own healing process as a method of saving the limb and improving quality of life.

For more information please visit: www.dfcon.com



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The Angiogenesis Foundation was represented among the nation’s foremost leaders and policy makers involved in The National Call to Action on Cancer Prevention and Survivorship in Washington D.C. yesterday. The National Call to Action on Cancer Prevention and Survivorship unites leaders in the medical community with government policymakers to advance the discussion on how to leverage innovation in order to advance cancer prevention and improve survivorship.
 
The National Call to Action on Cancer Prevention and Survivorship aims to promote healthy, cancer preventing lifestyles, apply what is known about cancer screening and early detection to all people, ensure the healthcare system is accessible and easy to navigate, and provide survivorship plans and support to all those affected by cancer. With similarly aligned goals, The Angiogenesis Foundation is proud to be a part of the national discussion and work with other members of The National Call to Action to ensure stakeholders from all sectors of society view the continuum of cancer prevention and survivorship as a national priority.... Read More

Ohio State University cancer researchers have developed a tumor-attacking virus that both kills brain tumor cells and blocks the growth of new tumor blood vessels, or angiogenesis. Their research, published online in the journal Molecular Therapy, shows that viruses designed to kill cancer cells — oncolytic viruses — might be more effective against aggressive brain tumors if they also carry a gene for a protein that inhibits tumor blood vessel growth.

The protein, called vasculostatin, is a naturally occurring angiogenesis inhibitor produced in the brain. In the study, an oncolytic virus containing the gene for vasculostatin in some cases eliminated human glioblastoma tumors growing in animals, and significantly slowed tumor recurrence in others. Glioblastomas, which characteristically have a high number of blood vessels, are the most common and devastating form of human brain cancer. People diagnosed with these tumors survive less than 15 months on average after diagnosis.... Read More

Patients with chronic myocardial ischemia (CMI) suffer the most severe form of coronary disease. In this condition, the blockages of coronary vessels feeding the heart are so severe, or the patients are so sick, that they have few or no options for treatment or improvement. Therapeutic angiogenesis is a new approach aimed at stimulating the growth of new blood vessels (angiogenesis) into the sickest areas of the heart, thus replenishing the vital blood supply. In laboratory studies, this approach has been shown to successfully treat heart disease, stroke, and impaired blood flow to the legs, or peripheral arterial disease.

Now, the largest national stem cell study in patients with CMI has shown the first evidence that transplanting a potent form of angiogenesis-stimulating adult stem cells into the heart muscle of subjects with severe angina — chest pain due to blocked coronary arteries — results in less pain and an improved ability to walk. The group of patients who received these cells also experienced fewer deaths than those who didn't receive stem cells. Findings were presented on November 17 at the American Heart Association Scientific Sessions 2009 in Chicago. The study was supported by Baxter Healthcare Corporation.... Read More

Using routine computed tomography (CT) imaging to analyze form and structural changes to colorectal liver metastasis after treatment with bevacizumab (Avastin) and chemotherapy may predict overall survival, according to research from The University of Texas M. D. Anderson Cancer Center. The findings are published in the Dec. 2 issue of the Journal of the American Medical Association (JAMA).

When combined with chemotherapy, the angiogenesis inhibitor bevacizumab is associated with both improved survival in patients with metastatic colorectal cancer and higher rates of pathologic response in patients undergoing surgical removal of colorectal liver metastases. Bevacizumab, a monoclonal antibody that blocks a key angiogenic protein, was approved for use in the front line setting of metastatic colorectal cancer in 2004.... Read More

Anthocyanins are naturally occurring pigmented chemicals belonging to the group of molecules called polyphenols found in green tea, many kinds of berries and fruits, and spices, such as curcumin.

These compounds have been shown to possess chemopreventive activity against a variety of cancerous tumors in preclinical studies, including tumors of the gastrointestinal tract. The cancer preventive properties are believed to be attributable to both their antiangiogenic effect, preventing tumors from developing a blood supply, as well as direct anti-tumor activity.... Read More

The U.S. Food and Drug Administration (FDA) has approved the antiangiogenic drug bevacizumab (Avastin), in combination with interferon-alpha, a type of immunotherapy, for people with metastatic renal cell carcinoma, the most common form of kidney cancer. According to the American Cancer Society, kidney cancer is the eighth most commonly diagnosed cancer in the United States. In 2009, approximately 57,760 Americans will be diagnosed with kidney cancer, and nearly 13,000 will die from the disease1.

Kidney cancer is the uncontrolled growth of cancerous cells that originate in the kidneys without a known cause. Nine out of 10 people with kidney cancer have renal cell carcinoma. Malignant kidney tumors churn out high amounts angiogenic growth factors, which stimulate the growth of new blood vessels (angiogenesis) that provide the tumors with oxygen and micronutrients. Bevacizumab, a monoclonal antibody, blocks VEGF (vascular endothelial growth factor), the primary mediator of angiogenesis in solid tumors, including renal cell carcinoma. Three other inhibitors of angiogenesis—sorafenib (Nexavar), sunitinib (Sutent), and temsirolimus (Torisel)—are approved to treat advanced kidney cancer, but target different parts of the angiogenesis process.... Read More

A Kansas State University researcher is studying the potential health benefits of a specially bred purple sweet potato with anti-cancer properties. Soyoung Lim, a doctoral student, and Dr. George Wang, Associate Professor of Human Nutrition at Kansas State, bred purple sweet potatoes to contain unusually high amounts of anthocyanin, a pigment that renders the purple hue in the vegetable. Anthocyanins can be red, blue or purple depending on the source's chemical structure, and are also found in foods such as blueberries, black raspberries, red grapes and red cabbage. Anthocyanins are known to have antiangiogenic properties, and high intake of foods containing this family of molecules has been associated with a reduced cancer risk in epidemiology studies.

Lim used a sweet potato with pronounced purple flesh and skin that was originally developed by Kansas State’s Ted Carey, Professor of Horticulture, at the University’s John C. Pair Horticultural Center in Haysville. Three different varieties of purple sweet potatoes, including Kansas State’s, were tested. Each contained varying amounts of anthocyanin. To quantify the amount of anthocyanin in each potato, Lim extracted the pigments from the vegetables and analyzed them via HPLC-MS Analysis, a method that separates the individual components. The potatoes were then segregated by flesh pigmentation and fiber content. ... Read More

Treatment with the angiogenesis inhibitor bevacizumab (Avastin®) improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2), a genetic tumor disorder, according to a new study conducted at the Massachusetts General Hospital (MGH) in Boston. Bevacizumab treatment successfully shrank tumors in a group of NF2 patients, which makes the antiangiogenic approach the first successful NF2 treatment not involving surgery or radiation. The findings are published in the July 23, 2009 issue of the New England Journal of Medicine.

NF2 is an uncommon inherited disorder in which benign tumors develop throughout the nervous system. The most common tumor is the vestibular schwannoma, which forms in the inner ear. Although it is slow growing, patients with these tumors often lose all or most of their hearing by young adulthood or middle age. The tumors can be removed surgically or treated with radiation, but such treatment usually leads to complete hearing loss, especially when tumors grow in both ears. Growing vestibular schwannomas can also press on the brainstem, leading to headaches, difficulty swallowing and other serious neurologic symptoms.... Read More

Patients with advanced kidney cancer—traditionally one of the most difficult-to-treat of all cancer types—are being given new hope in the form of drugs that inhibit tumor angiogenesis, or new blood vessel growth. Two antiangiogenic agents, sunitinib (Sutent®) and sorafenib (Nexavar®), have been FDA approved to treat advanced forms of the disease, including kidney cancer that has spread to other organs. These therapies, which are administered as pills, interfere with the chemical signaling between tumors and blood vessels, thereby blocking angiogenesis and essentially starving the tumor of oxygen and nutrients. A landmark clinical study published in 2007 showed that sunitinib dramatically prolongs the amount of time a patient lives without his/her disease getting worse, a benefit known as improved progression-free survival (PFS)1.

While these findings established sunitinib as a new standard of care for advanced kidney cancer, many patients considered by oncologists to have a “poor prognosis”, such as the elderly and those with brain metastasis or other disease features that often negatively impact treatment outcome, were excluded from the original clinical trial. Now, results from a multinational, expanded access study shows that sunitinib prolongs overall survival (OS) as well as PFS, and is safe and well tolerated in many advanced kidney cancer patients with a poor prognosis2. The new findings will be published in the August issue of the international medical journal Lancet Oncology.... Read More

Retinal vein occlusion (RVO) is a common and serious cause of vision loss that affects an estimated 684,000 people each year in the United States. The loss of vision occurs when blood flow through a retinal vein becomes blocked, such as by a blood clot. The blockage causes swelling under the retina, called macular edema, and hemorrhages in the retina itself. Sudden blurring or vision loss in all or part of one eye is common with RVO. Branch RVO occurs when one of the branches of the main vein of the eye becomes blocked, while in central RVO the blockage occurs in the main vein of the eye, located at the optic nerve.

A significant advancement for the treatment of RVO has now been achieved. A phase 3 clinical trial showed that treatment with the angiogenesis inhibitor ranibizumab (Lucentis®) can improve vision in patients with macular edema due to branch RVO. Ranibizumab, which is already approved as an antiangiogenic treatment for age-related macular degeneration (AMD), is a monoclonal antibody targeting the protein VEGF (vascular endothelial growth factor), a primary mediator of angiogenesis in eye diseases and other conditions, including cancer. In people with RVO and AMD, VEGF causes blood vessels in the eye to leak and proliferate abnormally, causing hemorrhages that gradually destroy vision. Anti-VEGF therapies, such as ranibizumab, inhibit the growth of these vessels, and can halt or even reverse vision loss in patients. ... Read More

People affected by Down syndrome rarely develop cancer. In fact, the overall cancer mortality in people with Down syndrome is less than 10 percent of that in the general population. Until recently, the explanation for this remained unknown.

“The body is packed with naturally occurring inhibitors of angiogenesis,” says Dr. William W. Li, President and Medical Director of the Angiogenesis Foundation. “So, observations like those in people with Down syndrome lead us to search for underlying biological reasons, such as the existence of elevated levels of molecules that inhibit blood vessel growth.”... Read More

The FDA has approved the drug toceranib (Palladia), a new medication that interferes with the formation of tumor blood vessels (angiogenesis), for use by veterinarians to treat pet dogs with mast cell cancer. This is the first cancer agent specifically approved for use in dogs. The drug comes in pill form and is expected to be available in early 2010.

According to the Angiogenesis Foundation, there are more than 6 million pet dogs diagnosed with cancer each year in the United States alone. Mast cell tumors are the second most common type of canine cancer. These tumors usually first appear under the skin, but they can also occur as primary tumors in the intestines, liver and spleen. Mast cell tumors are often aggressive, metastasizing to distant organs and lymph nodes, resulting in disseminated disease and death.  Prior to toceranib, the standard treatment of dogs with mast cell tumors usually involved surgical excision followed by radiation and/or chemotherapy for metastatic disease. However, dogs with disseminated mast cell cancer rarely survive beyond 6 months after diagnosis, even with aggressive therapy.

Toceranib belongs to a class of cancer agents called tyrosine kinase inhibitors (TKIs)—molecules that bind to cell surface receptors on tumors and their blood vessels to inhibit their growth and spread. Toceranib is designed to target a specific tumor cell receptor called c-Kit, which is mutated in 25-50% of canine mast cell tumors, and two other blood vessel cell receptors involved in tumor angiogenesis, PDGFR and VEGFR¹.

The efficacy of toceranib was evaluated in a double-blinded, placebo-controlled study involving 145 dogs with recurrent mast cell tumors with or without lymph node involvement². Dogs received either toceranib (3.25 mg/kg orally every other day) or placebo tablets. Dogs in the placebo group that experienced disease progression were permitted to receive toceranib. The objective response rate was 37.2% in dogs treated with toceranib, almost 5-fold greater than when compared placebo-treated dogs, with just a 7.9% rate (P=0.0004). Dogs whose tumors tested positive for a c-Kit mutation were twice as likely to respond to toceranib than those without the mutation (60% vs. 31.3%; P=0.0099). When the analysis was modified to include dogs originally in the placebo group, but that were then allowed receive toceranib, the objective response rate increased to 43%. Treatment with toceranib did not significantly compromise quality of life.  Dogs that responded to the drug had higher quality of life scores than those that did not. 

“This is a major leap forward for veterinary medicine,” said Dr. William Li, President and Medical Director of the Angiogenesis Foundation. “Eighty percent of dog cancers are identical to their human counterparts, so it makes complete sense that the antiangiogenic treatment approach that works in human cancers would also help dogs.” 

The Angiogenesis Foundation pioneered the first use of antiangiogenic therapies in canine cancers in 2000. Foundation researchers, working with veterinarians, developed a cocktail of human drugs suitable for dogs. Named the ‘Navy Protocol’ after a Golden Retriever that first received the treatment, the cocktail has been used to treat more than 600 dogs representing 32 breeds with 26 advanced tumor types.  Since 1995, the Foundation has been educating veterinarians and pet owners about the principles of angiogenesis and its promise for conquering cancer in dogs and other animals.

“We anticipate the success of toceranib will open new gateways for angiogenesis research to help animals,” said Dr. Li. “Now, man’s best friend can be treated as well as man himself.”

To learn more about angiogenesis in animal health or about the Foundation’s work in veterinary research, contact: vetmed@angio.org.

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Hereditary hemorrhagic telangiectasia (HHT) is an angiogenesis-dependent genetic disorder characterized by small vascular malformations (telangiectasia) in the skin and mucosal linings, and symptoms including nosebleeds, gastrointestinal bleeding, and iron-deficiency anemia. Internal organs can harbor malformations in larger vessels, called arteriovenous malformations (AVMs), which can result in serious bleeding episodes. HHT is a disorder of unbalanced angiogenesis. Patients have elevated plasma and tissue expression of vascular endothelial growth factor (VEGF)—the primary mediator of angiogenesis—and transforming growth factor-beta (TGF-b), which stimulates production of VEGF.

In a letter in the May 14, 2009 issue of the New England Journal of Medicine, Prithviraj Bose, M.D., and colleagues from the University of Oklahoma Health Science Center reported on the treatment of a 42-year old man with HHT using the antiangiogenic drug bevacizumab (Avastin), a humanized monoclonal antibody designed to neutralize VEGF. After treatment with 4000 mg of intravenous iron over a 6-month period, the patient received 4 cycles of bevacizumab every 2 weeks at a dose of 10 mg/kg for the first 2 cycles, and 5 mg/kg for the second two. After bevacizumab therapy was initiated, the patient’s nosebleeds decreased from 3-4 episodes per day pre-therapy to only 1-2 episodes per week. After completion of 12 weeks of treatment, the number of nosebleeds stabilized at 1-2 per day, but were of much shorter duration than pre-treatment (~10 min. vs. 30-45 min.). Serum ferritin (iron) levels increased from an average of 33 ng per mL in the 6 months prior to bevacizumab treatment to an average of 315 ng per mL in the 9 months after treatment was started. One-year follow-up of the patient indicates that the beneficial effects of bevacizumab in HHT may require maintenance therapy.

Two other cases of bevacizumab use in HHT have been reported. A patient with the condition receiving the agent for malignant mesothelioma had a dramatic reduction in GI bleeding due to AVMs; a second patient with severe hepatic HHT who received 6 courses of bevacizumab no longer required liver transplant and was doing well 6 months after completing treatment.

It should be noted that bevacizumab is not approved for the treatment of HHT or mesothelioma, and the cases described in these research reports represent off-label use of the agent.

For more information on HHT, visit www.HHT.org.

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British scientists have found that human fetal stem cells can effectively treat leg ischemic ulcers in a mouse model of Type 1 diabetes. They also discovered that the culture broth in which the stem cells had been grown mimicked the wound-healing ability of the cells, suggesting these cells may also serve as a "factory" of wound-healing substances. Alternatively, the active ingredients in the culture, once identified, could be used in place of the cells to avoid ethical concerns. The results were published online April 2 ahead of print in the journal Circulation Research.

Ischemic foot ulcers in diabetic patients have the worst outcome of all chronic skin wounds, with high amputation and mortality rates in patients with ischemic limbs. Impaired wound healing in diabetic patients results from multiple deficits, including deficient angiogenesis and impaired cell proliferation. The unique healing activity of stem cells is likely due to their ability to differentiate into the various component cells of injured tissues, as well as to produce and release growth factors that encourages the formation of new blood vessels (wound granulation). Transplantation of fetal stem cells may stimulate angiogenesis and promote tissue regeneration.

Paolo Madeddu, Professor of Experimental Cardiovascluar Medicine, and colleagues at the Bristol Heart Institute, UK, previously used fetal stem cells in a non-diabetic mouse model of limb ischemia. They showed that transplantation of a small number of CD133+ human fetal aorta-derived vascular progenitor cells promote revascularization and muscle cell regeneration, thereby supporting limb salvage. They also observed that the fetal stem cells secrete large amounts of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis.

The current study in a diabetic model of limb ischemia confirmed the previous findings that the CD133+ cells promote blood vessel formation and salvage the diabetic limb. Three days following the graft, consisting of a piece of collagen mixed with CD133+ stem cells, very few CD133+ cells were themselves detected in the ischemic diabetic ulcer. This indicated that the transplanted cells were not persistent, but has served their role in the very first days after transplantation. The CD133+ cells also released large amounts of growth factors and cytokines with pro-angiogenic and pro-survival potential.

To confirm the importance of these released factors, Professor Madeddu and colleagues grew the CD133+ cells in vitro, and then used the "conditioned" culture to reproduce the effects on wound healing and angiogenesis. These additional experiments confirmed that wound healing and angiogenesis are equally supported either by giving stem cells or the released products from these cells. To determine which components of the healing cocktail were the most active, they eliminated likely candidates one by one using blocking antibodies. Notably, they found that the VEGF and some interleukins were the crucial factors accounting for the healing effect of transplanted stem cells.

Importantly, VEGF was recognized to be responsible for reactivation of fetal genes belonging to the Wnt gene family in wounded tissues. Withdrawal of Wnt gene products also prohibited the beneficial action of conditioned medium on wound closure and reparative angiogenesis. It is known that fetal wounds heal in a scarless fashion. It is therefore possible that, when fetal stem cells are transplanted onto diabetic ulcers, they might reactivate an intrinsic fetal program in the recipient that allows adult ulcers to undergo repair in similar ways as fetal wounds do.

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Asian American women who ate higher amounts of soy during childhood had a 58% reduced risk of developing breast cancer, according to a National Cancer Institute study published in the April issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research(1). The study focused on women of Chinese, Japanese and Filipino descent living in San Francisco-Oakland, Los Angeles and Hawaii. Researchers interviewed 597 women with breast cancer and 966 healthy women. If the women had mothers living in the United States, researchers interviewed those mothers to determine the frequency of soy consumption in childhood of their offspring.

Historically, breast cancer incidence rates have been 4 to 7 times higher among white women in the U.S. compared to in women in China or Japan. However, when Asian women migrate to the U.S., their breast cancer risk rises over several generations to reach that of U.S. white women, suggesting that modifiable factors, such as diet, rather than genetics, are responsible for the international differences. Previous studies have suggested a protective effect of soy consumption in adults, but the results have been inconsistent. This was the first study to examine the role of childhood soy intake and breast cancer risk.

Researchers divided childhood soy intake into thirds and compared the highest and lowest groups. High intake of soy (>1.5 times/week) during childhood (age 5-11 years) was associated with a 58% reduction in breast cancer. A high level of soy intake in adolescent and adult years was associated with a smaller reduction of 20-25%. The childhood relationship held for all three races (Japanese, Chinese, Filipino), all three study sites (San Francisco-Oakland, Los Angeles, Hawaii), and in women with and without a family history of breast cancer. "Since the effects of childhood soy intake could not be explained by measures other than Asian lifestyle during childhood or adult life, early soy intake might itself be protective," said the study's lead investigator, Larissa Korde, M.D., M.P.H., a staff clinician at the NCI's Clinical Genetics Branch.

According to Dr. Korde, her study suggests early soy intake may have a biological role in breast cancer prevention. "Soy isoflavones have estrogenic properties that may cause changes in breast tissue. Animal models suggest that ingestion of soy may result in earlier maturation of breast tissue and increased resistance to carcinogens," she said. “This study builds upon the evidence that the antiangiogenic molecules present in soy may be useful for preventing cancer,” said Dr. William W. Li, President and Medical Director of the Angiogenesis Foundation, Cambridge, Mass. “It was shown over a decade ago that the urine of Buddhist monks who consumed soy-based diets contained high levels of genistein, a naturally-occurring angiogenesis inhibitor.”

Notably, genistein exhibits a dose-dependent inhibition of vascular endothelial growth factor (VEGF), a potent angiogenesis stimulator, as well platelet-derived growth factor (PDGF), tissue factor, and matrix metalloproteases, which also promote angiogenesis(2).  Several antiangiogenic drugs designed specifically to inhibit VEGF and PDGF are already FDA-approved to treat colon, kidney, liver, brain, breast, and lung cancers. “This new study is the first to provide strong evidence for a preventative role of soy consumption during childhood,” said Dr. Li.

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Two recent studies suggest that naturally occurring antiangiogenic molecules present in black raspberries and licorice may have a role in preventing some types of cancer. In the first study published in the journal Cancer Prevention(1), researchers at the Ohio State Comprehensive Cancer Center found that anthocyanins, a class of flavonoids present in many types of berries, as well as red wine, inhibited tumor growth and angiogenesis, and stimulated cancer cell death in the experimental rats treated with a potent esophageal carcinogen.

Dr. Gary D. Stoner and colleagues fed rats an anthocyanin-rich extract of black raspberries and found that the extract was nearly as effective in preventing esophageal cancer in rats as whole black raspberries containing the same concentration of anthocyanins. In addition to reducing markers of inflammation and cell proliferation in the esophagus, the anthocyanins suppressed the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1alpha). The VEGF protein is a primary stimulator of tumor angiogenesis, and upregulation of HIF-1alpha is considered an initiating step in the angiogenesis cascade. Inhibitors of VEGF are already used, as drugs, to treat a variety of cancers as well as blinding disorders. According to the Angiogenesis Foundation, the opportunity to utilize dietary sources of naturally-occurring angiogenesis inhibitors to modify or prevent disease is an important new frontier for the angiogenesis field.

"Now that we know the anthocyanins in berries are almost as active as whole berries themselves, we hope to be able to prevent cancer in humans using a standardized mixture of anthocyanins," said Dr. Stoner. "The goal is to potentially replace whole berry powder with its active components and then figure out better ways to deliver these components into tissues to increase their uptake and effectiveness. Ultimately, we hope to test the anthocyanins for effectiveness in multiple organ sites in humans.”

In the second study related to dietary antiangiogenesis, researchers at Vanderbilt University Medical Center showed that inhibiting an enzyme called 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) by treatment with a natural compound found in licorice prevents colorectal cancer progression in mice. The study was published in the April issue of the Journal of Clinical Investigation(2).

The Vanderbilt researchers examined expression of 11βHSD2 in human colon polyps and in the colons of mice predisposed to colon cancer. They found that 11βHSD2 was increased in polyps found in both mice and humans and correlated with COX-2 expression and activity. They then inhibited 11βHSD2 with glycyrrhizic acid, the main sweet-tasting component of licorice, and also by silencing the gene for 11βHSD2. Both treatments inhibited the production of prostaglandin E2 and prevented the development of polyps (adenomas) and tumor growth and metastasis. Because 11βHSD2, which modulates the inflammatory enzyme COX2-, is highly expressed only in kidney and colon, blocking the enzyme produces effects specific to those tissues.

"Since studies here and elsewhere have shown the importance of COX-2 and colonic carcinogenesis, we postulated that maybe one of the mechanisms by which the normal colon might prevent excessive expression of COX-2 is by 11βHSD2," said Dr. Raymond Harris, the Ann and Roscoe R. Robinson Professor of Nephrology of Vanderbilt University Department of Medicine, and an author on the study.

Licorice, Dr. Harris noted, has been used as a nutraceutical for thousands of years for ailments ranging from coughs to constipation. In addition to inhibiting COX-2 through 11βHSD2, licorice also contains isoliquiritin, a flavonoid that has been shown to inhibit angiogenesis, vascular endothelial cell proliferation and capillary formation.

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The FDA's Oncologic Drugs Advisory Committee (ODAC) unanimously recommended accelerated approval for bevacizumab (Avastin) for the treatment of glioblastoma multiforme (GBM), an aggressive and nearly uniformly fatal form of brain cancer. The drug's manufacturer, Genentech, is seeking an indication for bevacizumab as monotherapy for previously treated GBM patients. The panel’s vote of 10-0 for approval was based on results of two phase 2 studies of bevacizumab in GBM.

In one of the studies involving 167 patients with treatment-refractory GBM, bevacizumab monotherapy (10 mg/kg every two weeks) resulted in a partial response rate of 26%, with median a median response duration of 4.2 months. No patients in the study had a complete response. The 6-month progression free-survival rate was 36%, and one-year overall survival was about 38%. Historically, among patients with progressive GBM who receive salvage chemotherapy, on average only about 25% remain alive at one year.

The other study, which involved 56 patients with previously treated high-grade gliomas, produced an objective response rate of 20% and a median duration of response of 3.9 months.

Treatment response in GBM is difficult to assess because the disease disrupts the blood-brain barrier, which often creates significant brain edema. This shows up as increased contrast enhancement on MRI. Bevacizumab reduces the leakiness of blood vessels surrounding the tumor, and consequently improves contrast enhancement. It is unclear, however, to what extent this effect may represent a true anti-tumor response, a concern cited by the FDA panel. There is some evidence that GBM may continue to progress even in the presence of reduced edema. Nonetheless, the advisory panel found the trial results compelling enough to unanimously recommend approval.

The FDA is not obligated to follow advisory committee recommendations, but usually does so. A final agency decision is expected by early May.

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Preliminary data from the largest CD34+ adult stem cell study for heart disease has shown the first evidence that delivering a potent form of autologous (patient-derived) adult stem cells into the heart muscle of patients with severe angina (chest pain due to blocked arteries) may result in less pain and improved exercise tolerance. The stem cells contribute to forming new angiogenic blood vessels that provide critical blood flow to oxygen-starved heart tissue. The findings were presented on March 28 as a late-breaking abstract at the American College of Cardiology's 58th annual scientific session in Orlando.

The prospective phase II, randomized, double blind, placebo-controlled, multi-center study included 167 adult patients who were on maximal medical therapy and were not suitable candidates for conventional procedures to improve blood flow to the heart, such as angioplasty, stents, or coronary artery bypass surgery. All patients were given a drug to stimulate release of CD34+ adult stem cells from the bone marrow; these cells were then collected from the bloodstream using a process called apheresis, and then separated from the other blood components.

The CD34+ adult stem cells were injected into 10 locations in the heart muscle of patients in the treatment group. Patients in the placebo group received saline injections. Researchers used a sophisticated electromechanical mapping technology to identify where the heart muscle was alive but not functioning because it was not receiving enough blood supply. “In this situation, the muscle hibernates because it wants to decrease energy consumption to stay alive," explained principal investigator Douglas Losordo, M.D. "It's not getting enough oxygenated blood to perform normally, so it shuts down its contractile function."

After the procedure, the autologous stem cell transplant patients were able to walk longer on a treadmill (60 seconds on average) than those in the placebo group. It also took longer until they experienced angina pain on a treadmill compared to the placebo group and, when they felt pain, it went away faster with rest. In addition, stem cell-treated patients had a reduction in the number of episodes of chest pain compared to the control group.

"The results from this study provide the first evidence that a patient's own stem cells could actually be used as a treatment for their heart disease," said Dr. Losordo, who is also the Eileen M. Foell Professor of Heart Research at the Feinberg School of Medicine and of the Program in Cardiovascular Regenerative Medicine at Northwestern Memorial Hospital. Northwestern Memorial Hospital was the lead site of the study, which was sponsored by Baxter International Inc. "The study provides potential hope for those patients with currently untreatable angina to be more active with less pain."

According to the Angiogenesis Foundation, about 300,000 out of the estimated one million people in the U.S. who suffer from chronic, severe angina cannot be helped by traditional medical treatment. The patients in the study were Canadian Classification System (CCS) class 3 or 4, meaning they experienced chest pain while performing normal to minimal activities such as brushing their teeth, or even while at rest. New treatments that stimulate coronary angiogenesis are a highly promising approach to this debilitating and life-threatening condition."

"In addition to the new vessels that adult stem cells help grow," stated William Li, M.D., President and Medical Director of the Angiogenesis Foundation, "this approach is likely to bring in crucial survival factors that promote recovery and possibly even regeneration of damaged heart tissue."

Dr. Losordo cautions that the findings of the 26-site trial, while encouraging, are not yet definitive and require verification in a larger randomized study. Analysis of this study’s efficacy at 12 months is pending.

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German researchers have found that high circulating levels of angiopoietin-2 (Ang-2), a naturally occurring angiogenesis stimulator, correlates with tumor progression and reduced survival in patients with advanced (stage III and IV) melanoma. The findings were published in the February 15, 2009 issue of the journal Clinical Cancer Research.

The docking station of Ang-2 is the receptor Tie2 on the surface of endothelial cells, which form the inner lining of blood vessels. The angiopoietin/Tie system regulates the later stages of angiogenesis by controlling endothelial cell survival and vessel maturation.

Researchers, led by Dr. Hellmut Augustin and Prof. Dirk Schadendorf of DKFZ and Mannheim Medical Faculty of the University of Heidelberg, measured Ang-2 concentrations in blood samples of melanoma patients. They discovered that larger tumors and more advanced disease stages correlate with high levels of Ang-2; if one tracks the Ang-2 levels of individual patients over time, an increases occurs in parallel to disease progression. In contrast, patients who have lived with the disease for a long time, i.e., whose disease was not, or only slightly progressive, had lower Ang-2 levels. The researchers found that Ang-2 concentration in blood serum is a more precise indicator of the progression and stage of the disease than previously used biomarkers.

This close association between melanoma progression and Ang-2 levels prompted the question of whether Ang-2 only stimulates vascularization in the tumor or whether it has additional influence on the behavior of the actual cancer cells. Such an effect had not yet been proposed for any one of the various growth factors that act on the cells of the vascular walls. In this study, melanoma cells were found to produce both soluble Ang-2 and the matching receptor, Tie2, on their own cell membranes, which meant they were theoretically capable of self-activation.

To test this hypothesis, researchers genetically silenced the Ang-2 expression in some of the melanoma cells and compared them against control cells. Test systems in the culture dish subsequently revealed that the melanoma cells had lost their ability to migrate—the migration tendency of cancer cells is regarded as important information about their ability to invade other tissue in the body and metastasize.

Advanced melanoma therefore appears to use the Ang-2/Tie2 signaling system to strengthen its malignant properties. "Ang-2 is a very promising therapeutic candidate, both as a biomarker for better monitoring disease progression and as a target structure for therapy," said lead author Hellmut Augustin. “Therapies that block Ang2 might not only attack the tumor's blood supply, but also reduce its malignant growth.”

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New research indicates that tumor blood vessels contain a protein sensor that detects minute changes in oxygen levels in tissues. These tumor vessels respond to the changes by becoming either more or less porous, which significantly influences the ability of cancer cells to escape through capillary walls and spread as metastases to distant organs. The findings are published in the March 6 issue of the journal Cell.

Massimiliano Mazzone and his colleagues, under the direction of Dr. Peter Carmeliet, at Katholieke Universiteit Leuven, Belgium, have shown that reducing activity of the oxygen sensor PHD2, which is normally increased in times of oxygen shortage (hypoxia), leads to the formation of a close-fitting, smooth, cobblestone-like lining of endothelial cells inside blood vessels. This contiguous row of cells resembles a 'phalanx'—the Greek military formation in which soldiers stand shoulder-to-shoulder with shields touching. This phalanx streamlines blood vessels, which improves the delivery of chemotherapy and other drugs into the tumor.

The researchers used mice genetically modified to have reduced levels of PHD2 and implanted them with different types of tumors. Compared to normal, wild-type mice, the tumor vasculature of the mice with reduced PHD2 expression had more normalized endothelial cells marked by tighter cell junctions. This change in architecture resulted in a significantly reduced propensity for metastasis and invasion.

The discovery of this protein function could lead to new angiogenesis-based treatments for cancer. As tumors grow they produce growth factors that stimulate the growth of new blood vessels to increase oxygen supply. These new tumor blood vessels have an abnormal structure, so tumors become hypoxic, which increases production of PHD2, loosening the phalanx and making the vessels more easy for cancer cells to escape from and metastasize to distant organs. In addition, the abnormal shape of the blood vessels restricts the delivery and effectiveness of chemotherapeutic agents.

PHD2-blockers may therefore offer new possibilities to combat cancer. By converting the abnormal endothelial layer into a phalanx of tightly aligned and impermeable cells, cancer drugs can penetrate the tumor more effectively. In addition, such a phalanx barrier may reduce metasases.

This research might also open new methods of treatment for other angiogenesis-dependent diseases such as wet age-related macular degeneration.

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Lowering serum cholesterol appears to suppress tumor angiogenesis and the growth of prostate tumors in mice, according to a new study appearing in the March 2009 issue of The American Journal of Pathology.

High cholesterol not only leads to atherosclerosis and heart disease, but may also contribute to cancer growth and progression. Prostate cancer is the most common non-skin cancer in the United States, affecting approximately 1 in 6 men. Prostate tumors accumulate high levels of cholesterol, and tumor incidence correlates with consumption of a high fat/high cholesterol diet "Western" diet. In addition, prostate tumor progression has been linked to serum cholesterol levels.

To examine the role of high cholesterol in prostate cancer, Dr. Keith Solomon and colleagues from Harvard Medical School, Children’s Hospital Boston, and Rutgers University used mice implanted with human prostate cancer xenografts. The mice were then divided into one of four groups: those fed high fat/high cholesterol "Western" diets with or without ezetimibe (Zetia™), a drug that blocks absorption of cholesterol from the intestine, and those fed low fat/no cholesterol diets with or without ezetimibe.

High cholesterol levels were significantly associated with greater tumor growth and increased angiogenesis. Notably, serum cholesterol was inversely correlated with levels of thrombospondin-1 (TSP-1), a potent endogenous inhibitor of angiogenesis—TSP-1 was suppressed in mice with high cholesterol and increased in those on low fat diets or that received ezetimibe. Other markers of angiogenesis were also affected by ezetimibe therapy. Mice treated with the drug had significant decreases in microvessel density, a marker of angiogenesis, and increased vessel pericyte coverage (suggesting a more stable vascular structure). Another finding was that high cholesterol levels were associated with greater numbers of fibroblasts in tumors; stromal fibroblasts have been shown to increase tumor angiogenesis through increased levels of stromal cell-derived factor-1.

The team found that over several weeks, nerve signal speed and sensitivity to temperature were restored to normal in diabetic mice injected with the bone marrow cells. A fraction of the bone marrow cells appear to become endothelial cells although many of them retain characteristics that make them look like white blood cells. However, they secrete molecules that stimulate the growth of both endothelial cells and Schwann cells, which protect and insulate peripheral nerves, the authors found.

"Lowering cholesterol levels whether through diet, exercise, or the use of safe cholesterol-lowering drugs is known to provide a substantial benefit to patients—in the future it may be possible to add reduced risk of serious prostate cancer to that list of benefits" said Dr. Solomon. "We are in the process of working with clinicians to translate these findings into potential human studies. If we can demonstrate the effects noted in our pre-clinical studies in human patients we may be save lives and improve the quality of life," added Dr. Michael Freeman, senior author of the study.

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A team of cancer researchers at the Research Institute of the McGill University Health Centre (MUHC) at the Montreal Children's Hospital has discovered a new mechanism by which cancerous tumors stimulate the growth of the blood vessels that feed them, a process called angiogenesis. These findings may lead to new ways to control this process, which could translate into future therapies. Results were published February 20th in the online edition of the Proceedings of the National Academy of Sciences (PNAS).

Scientist have known that tumor cells can release "bubbles" called microvesicles containing various substances that allow the tumor to communicate with other tumor cells and with endothelial cells lining blood vessels, and stimulate changes in their behavior. In the new study, researchers identified microvesicles armed with the receptor for endothelial growth factor (EGFR), a key receptor tyrosine kinase involved in angiogenesis and tumor growth. Researchers used human squamous cell carcinoma cell lines to demonstrate the microvesicular transfer of EGFR from the tumor cells to endothelial cells.

They then showed that the endothelial cells that received the EGFR increased their production of vascular endothelial growth factor (VEGF), the primary stimulator of angiogenesis, and expression of VEGF-receptor-2 (VEGFR-2). Essentially, the microvesicle-derived EGFR re-wired the endothelial cells to express and respond to VEGF in an autocrine manner, a potentially important step in tumor angiogenesis.

"We had already demonstrated the existence of these vesicles as well as their importance in the communication process between cancer cells and their environment. But this new discovery is much more targeted and represents a new direction in terms of therapy," said study author Dr. Janusz Rak.

Notably, by blocking the microvesicle exchange using Diannexin, a derivative of annexin V, researchers inhibited both tumor growth and angiogenesis. "The molecule we used is effective both in vitro and in vivo. It prevents the formation of new blood vessels in mice with cancer and therefore strongly inhibits tumor growth," said Dr. Rak.

Diannexin blocked the in vitro fusion of vesicles and endothelial cells. In mice with cancer, Diannexin slowed blood vessel growth towards the tumor, resulting in anti-cancer effects. This finding is particularly important considering the treatment was applied in isolation without additional chemotherapy. If combined with other agents, this new way of treating cancer may be even more potent. Diannexin is also currently being developed as an antithrombotic medication.

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Transplanting cells that replenish blood vessels can also restore nerve function in an animal model of diabetic neuropathy, Emory researchers have found. The results are described in the February 10th issue of the journal Circulation.

The majority of people with diabetes have some form of neuropathy—damage to the peripheral nerves that can cause a loss of sensation in hands, arms, feet or legs. The damage, caused by high blood sugar, occurs gradually and in advanced cases can lead to amputation. Scientists have connected the damage to problems with peripheral nerves' blood supply.

Cultured cells from the bone marrow can promote the regrowth of both blood vessels and the protective lining of nerves in the limbs of diabetic animals, a team led by Young-sup Yoon, MD, PhD, associate professor of medicine (cardiology) at Emory University School of Medicine, found.

Bone marrow contains endothelial progenitor cells (EPCs), which can divide into endothelial cells, and help grow new blood vessels, a strategy which is being developed for patients with heart disease and circulatory compromise of the legs. In diabetes the number and function of EPCs is known to be diminished. Yoon's team cultured bone marrow cells in a way designed to enrich them for EPCs and injected them next to the sciatic nerves of diabetic mice. The sciatic nerve is a large nerve that runs from the back to the rear leg. The mice were made diabetic by giving them streptozocin, a drug that destroys insulin-producing cells in the pancreas.

The team found that over several weeks, nerve signal speed and sensitivity to temperature were restored to normal in diabetic mice injected with the bone marrow cells. A fraction of the bone marrow cells appear to become endothelial cells although many of them retain characteristics that make them look like white blood cells. However, they secrete molecules that stimulate the growth of both endothelial cells and Schwann cells, which protect and insulate peripheral nerves, the authors found.

"We were surprised to find that in this specific environment, they engraft and survive longer than in other tissues," Yoon says. "These cells appear to home to peripheral nerves."

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Researchers from The University of Texas M.D. Anderson Cancer Center have found that increased angiogenesis and vascular endothelial growth factor (VEGF) expression are associated with poor survival in women with sex cord-stromal ovarian tumors. The data was presented at the 40th Annual Meeting on Women's Cancer of the Society of Gynecologic Oncologists, held from February 5-9 in San Antonio, Texas.

Sex cord-stromal ovarian tumors are rare, accounting for 5-7% of all ovarian cancer diagnosed, and information on how they spread has been limited. "These tumors tend to metastasize very differently from other, more common types of ovarian tumors," said Jubilee Brown, M.D., assistant professor in the Department of Gynecologic Oncology and lead author on the study. "For instance, sex cord-stromal tumor cells rarely break away and invade the lymph nodes, but we still see evidence of their spread to distant locations in the body such as the abdomen and liver. This unusual progression hinted that a different pattern of metastasis might be at play."

The new findings provide doctors with a greater understanding of how they may be able to use angiogenesis inhibition to successfully treat patients with this type of tumor, according to the study's authors. A number of antiangiogenic agents are approved to treat other tumor types, including cancers of the colon/rectum, breast, lung, liver, bone marrow and kidney. Dr. Brown is currently the principal investigator on a Gynecologic Oncology Group Phase II clinical trial at M.D. Anderson to test the efficacy of bevacizumab (Avastin), a humanized monoclonal antibody against VEGF, in patients with sex cord-stromal tumors.

In the study presented at the conference, researchers looked at 54 sex cord-stromal ovarian tumor samples—28 from women with primary occurrences and 26 from women with recurrences. The samples were evaluated for two common indicators of angiogenesis: VEGF expression and high microvessel density (MVD), or a large number of blood vessels associated with the tumor. Of those tumors studied, VEGF overexpression was noted in 52%, and high MVD was present in 32%. Both high MVD and VEGF were linked to significantly poorer survival (130 months vs. 415 months in those with high MVD and 154 months versus 394 months in those with VEGF overexpression). High MVD was also associated with recurrence and metastasis to the abdomen, liver, lung and bone.

"Unlike most ovarian tumors, which metastasize to nearby tissues or invade the lymphatic system, we suspect that the biological qualities of sex cord-stromal tumors, especially their ability to spread to and survive in distant sites of the body, explain why this type of ovarian cancer behaves so differently in patients," said Anil Sood, M.D., professor in the Departments of Gynecologic Oncology and Cancer Biology at M.D. Anderson and senior author on the study. "By honing in on how sex cord-stromal tumors utilize the blood vessels to become deadly, we can begin to test targeted antiangiogenic therapies as possible means to control their growth."

The American Cancer Society estimates approximately 21,650 new cases of ovarian cancer were diagnosed in the United States in 2008. There are more than 30 different types of ovarian cancer, categorized by the type of cell where the malignancy begins. Sex cord-stromal ovarian tumors, which develop in the connective tissue that holds the ovary together, are typically diagnosed at an earlier stage.

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New research published in the journal Brain, Behavior, and Immunity suggests that the use of commonly prescribed blood pressure medicines called beta-blockers might slow the development of malignant melanoma, a particularly aggressive form of skin cancer.

Researchers at the Ohio State University have been looking for links between stress hormones and diseases like cancer. Eric V. Yang, a research scientist at the Institute for Behavioral Medicine Research (IBMR), exposed samples of three melanoma cell lines to the compound norepinephrine, a naturally occurring catecholamine that functions as a stress hormone. In times of increased stress, levels of norepinephrine increase in the bloodstream.

Yang and colleague Ronald Glaser were looking for changes in the levels of three proteins released by the cells. One of the proteins – vascular endothelial growth factor (VEGF) – plays a key role in stimulating angiogenesis, or the growth of new blood vessels needed to feed a growing tumor. The other two proteins, Interleukin-6 and Interleukin-8, are both involved in fostering tumor growth.

All three of the cell lines were grown from tissues taken from secondary tumors that had metastasized from a primary site, and signify aggressive forms of cancer. But one of them – C8161 – represented the most aggressive and advanced form of melanoma.

"We noticed that all three of these proteins increased in response to the norepinephrine," Yang explained, adding that in the C8161 cells, "we got a 2,000 percent increase in IL-6. In untreated samples from this cell line, you normally can't detect any IL-6 at all. What this tells us is that stress might have a worse effect on melanoma that is in a very aggressive or advanced stage, and that one marker for that might be increased levels of IL-6," he said.

The researchers ruled out cell proliferation – an increase in the number of cells present – as a reason for the increase in all three proteins. That meant that the only other answer was that the cells were increasing their expression of the genes responsible for producing these compounds. Their experiments showed that the norepinephrine molecule binds to receptors on the surface of cancer cells, and once this linkage occurs it stimulates the release of the proteins that support angiogenesis and tumor growth.

Yang and Glaser first confirmed that the receptors were present on cells in all three cell lines and then tested what would happen when the receptors were blocked by common blood pressure medicine – the so-called "beta-blockers." When the beta-blockers did bind to the receptors, the production of the three proteins was reduced significantly, suggesting that in patients with melanoma, using these types of medications might be used to slow the progression of the disease.

While the study was restricted to tumor cell lines grown in the laboratory, the findings are still exciting. The researchers found strong evidence that the same receptors are expressed on the surface of tumor cells from biopsies that were taken from melanoma patients, which supports the clinical importance of the results.

Two earlier studies on different tumor cell lines – one prepared from a multiple myeloma and the other from a nasopharyngeal carcinoma – also showed that exposure to norepinephrine increased the levels of proteins responsible for accelerating tumor growth.

The research is showing not only that different forms of cancer react differently to stress hormones but also that those reactions can vary within a specific form of the disease, with the possibility of a more aggressive form of the disease reacting more strongly to the stressors.

For melanoma patients, that can be very important since these tumors are able to metastasize, or spread, when they are much smaller than most other solid cancers. The American Cancer Society estimates that nearly 48,000 cases of melanoma are diagnosed each year and nearly 8,000 people are killed each year by the disease.

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Researchers at the Johns Hopkins University School of Medicine have discovered how a whole class of commonly used chemotherapy drugs can block cancer growth. Their findings, reported online this week at the Proceedings of the National Academy of Sciences Early Edition, suggest that a subgroup of cancer patients might particularly benefit from these drugs.

The anthracycline class of chemotherapeutics — doxorubicin (Adriamycin), daunorubicin, epirubicin, idarubicin — have been used for four decades to treat many types of cancer, including leukemia, lymphoma, sarcomas and carcinomas, The standard method of administration had been to use the highest tolerable dose every few weeks to kill all rapidly growing cells by preventing them from accurately copying their genetic material. "But the late Judah Folkman discovered in 2000 that so-called metronomic treatment, giving patients lower doses of these drugs more frequently, can keep cancer growth at bay by blocking blood vessel formation, but the exact mechanism by which this occurred wasn't known," says Gregg L. Semenza, M.D., Ph.D., director of the vascular program at the Johns Hopkins Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine. "Now we've shown how it happens and what players are involved, which could help shape future clinical trials for patients with certain types of cancers."

Semenza and his team have long studied how the hypoxia-inducible factor, or HIF-1, protein helps cells survive under low-oxygen conditions. HIF-1 turns on genes that grow new blood vessels to help oxygen-starved cells, like those found in fast-growing solid tumors, survive. To look for drugs that can prevent new blood vessel growth, the team tested more than 3,000 already FDA-approved drugs in the Johns Hopkins Drug Library for their ability to stop HIF-1 activity. Using modified liver cancer cells growing in low oxygen, the team treated cells with each of the drugs in the library and examined whether the drug could stop HIF-1 from turning on genes.

One drug—daunorubicin—reduced HIF-1's gene-activating ability by more than 99 percent. They tested other members of the anthracycline drug class and found that doxorubicin, epirubicin and idarubicin also blocked HIF-1 activity. But further examination showed that both drug-treated and untreated cells contained similar amounts of HIF-1 protein, leading the researchers to conclude that the drugs are not affecting whether or not HIF-1 is made.

To turn on genes, HIF-1 must bind to DNA. So the research team looked at drug-treated and untreated cells and compared regions of DNA known to be bound by HIF-1. The sites that are bound by HIF-1 in untreated cells were found unbound in anthracycline treated cells. "We know that this class of drug prefers to bind to DNA sequences that are similar to the DNA sequence bound by HIF-1, but this is the first direct evidence that anthracyclines prevent HIF-1 from binding to and turning on target genes," says Semenza.

To see if the interference with HIF-1 binding to DNA affects cancer growth, the team grew tumors in mice from human prostate cancer cells. They treated these mice with daunorubicin, doxorubicin or saline once a day for five days and measured tumor size. Tumors in saline-treated mice nearly doubled in size in that time, whereas tumors in the drug-treated mice stayed the same size or became smaller. When the team examined the tumors from drug-treated mice, they found that the number of blood vessels was dramatically reduced compared to mice treated with saline. Additional tests revealed that the genes that HIF-1 turns on to drive blood vessel formation were turned off in tumors from the drug-treated mice.

"What this means, we hope, is that patients with a prostate cancer that has high HIF-1 levels — which puts them at greater risk of relapse following surgery or radiation therapy — might benefit from treatment with these drugs," says Semenza. "However, clinical trials are necessary to determine whether this approach will help keep cancer patients alive."

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Mice exposed to low temperatures develop more blood vessels in their adipose tissue and metabolise body fat more quickly, according to a new study published in the journal Cell Metabolism. Scientists now hope to learn how to control blood vessel development in humans in order to combat obesity and diabetes.

The growth of fat cells and their metabolism depend on oxygen and blood-borne nutrients. A possible way to regulate the amount of body fat – in order, for instance, to combat obesity – can therefore be to affect the development of blood vessels in the adipose tissue.

Researchers at Karolinska Institute have now demonstrated the rapid development of blood vessels in the adipose tissue of mice exposed to low temperatures. This is followed in its turn by a transformation of the adipose tissue from "white" fat to "brown" fat, which has higher metabolic activity and which breaks down more quickly.

"This is the first time it's been shown that blood vessel growth affects the metabolic activity of adipose tissue rather than vice versa," says Professor Yihai Cao, who led the study. "If we can learn how to regulate the development of blood vessels in humans, we'd open up new therapeutic avenues for obesity and metabolic diseases like diabetes."

Brown fat releases heat when it breaks down, and is mainly found in hibernating animals. In humans, it is found in newborn babies, but scientists believe by controlling blood vessel development that it might be possible to transform white fat to brown fat in adults as well

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In a new study published in the January 2009 issue of the journal Ophthalmology, Japanese researchers found high levels of inflammatory factors, including vascular endothelial growth factor (VEGF), the primary proangiogenic growth factor, in the vitreous of people with diabetic macular edema (DME). These findings may lead to the development of new treatments in people with the disease.

DME is a serious complication of diabetic retinopathy that typically develops over many years in people with diabetes. It impacts the retina, the area at the back of the eye that focuses images for transmission to the brain. Advanced complications of retinopathy include the growth of abnormal blood vessels on the retina and optic nerve, and DME, in which there is swelling of the macula at the center of the retina as fluid leaks from hyperpermeable blood vessels. Precisely how DME develops is unclear, but the condition is similar to chronic inflammation that can occur in other areas of the body. When inflammation occurs, the body's immune system releases chemical messengers into the blood or affected tissues in an attempt to rid the body of a perceived infection, irritant, or injury. Some of the chemicals cause leakage of fluid into the tissues, resulting in swelling.

Hideharu Funatsu, M.D. and colleagues at the Tokyo Women's Medical University, Japan, measured levels of four inflammatory factors and one anti-inflammatory factor in the vitreous gel, which fills the eye between the lens and the retina, of 53 patients with DME, 15 patients with nondiabetic ocular disease, and 8 diabetic patients without retinopathy. They selected for measurement VEGF, intercellular adhesion molecule (ICAM)-1, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, and the anti-inflammatory pigment epithelium-derived factor (PEDF) because earlier research had linked these factors to the development or exacerbation of DME.

Levels of all four inflammatory factors were significantly higher, and PEDF significantly lower, in the vitreous of in patients with DME compared with the two other patient groups. VEGF and ICAM-1 had a stronger influence on the severity of DME than the other factors. VEGF is a strong vascular permeability factor that is overproduced in response to reduced oxygen levels (hypoxia) in the retinas of people with retinopathy. It is also the primary stimulant of tumor blood vessel growth. Dr. Funatsu's research suggests VEGF is the key to the inflammatory response in DME. Building on earlier, similar findings, the study also indicates that PEDF may block the expression and actions of the key inflammatory factors.

Although this study suggests that intravitreal injection of steroids such as triamcinolone acetonide may be useful in treating DME, further clinical trials are required to confirm this finding.

"Triamcinolone acetonide down-regulates VEGF and ICAM-1, inhibits inflammatory cells, stabilizes cell membranes, and increases PEDF levels. It appears to control more of the cytokine messengers that contribute to abnormal blood vessel permeability," said Dr. Funatsu. He adds that further focus on VEGF and ICAM-1 may further illuminate the mechanisms of blood vessel breakdown in DME and lead to new treatments.

With a new study from the Centers for Disease Control and Prevention predicting that diabetic retinopathy will triple from 5.5 million in 2005 to 16 million in 2050, improved treatments are urgently needed for this leading cause of blindness in working-age people. The CDC study is the latest indicator of a worldwide diabetes epidemic that is motivating ophthalmic research around the globe. For more information, visit www.aao.org.

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