In 1989, Folkman developed a hypothesis that led to the discovery of the most potent angiogenesis inhibitors known. Some primary tumors, he knew, are able to suppress the growth of their remote metastases. Folkman hypothesized that while these tumors secrete short-acting, highly potent angiogenic stimulators locally, they simultaneously secrete low levels of long-lasting angiogenic inhibitors into the circulation. One such inhibitor, thrombospondin, had already been found to be secreted by tumor cells by Noel Bouck at Northwestern University.

Michael S. O'Reilly, M.D., pursued Folkman's idea, and ultimately purified three more inhibitor proteins from tumor-bearing animals: angiostatin in 1994, endostatin in 1996, and antiangiogenic antithrombin (aaAT) in 1998. These proteins caused animal tumors to regress to a microscopic size, where they often remained dormant indefinitely, even after prolonged therapy was discontinued. Another protein, 2-methoxyestradiol (2ME2), was reported by Robert D'Amato to be a potent angiogenesis inhibitor in 1994. This protein, a metabolite of estrogen, is found in women's urine near the end of pregnancy.

These novel proteins, occurring naturally in the body, have shown no toxicity. Moreover, tumors do not become resistant to them as they do to conventional chemotherapy agents. This is because the inhibitors don't target cancer cells, which develop resistance rapidly because of a high mutation rate, but instead target endothelial cells, which rarely mutate. Endostatin and angiostatin are now in Phase II clinical trials. Under the trade name Panzem, 2ME2 is in Phase I and Phase II trials for multiple myeloma, breast cancer, and prostate cancer. AaAT is still in development.

A variety of other drugs have recently been discovered to have unexpected anti-angiogenic effects. These include the anti-inflammatory drugs celecoxib and rofecoxib; rosiglitazone, a drug commonly used to treat Type 2 diabetes; and Erbitux, a drug initially designed to counter cancer-causing oncogenes. Even conventional chemotherapy drugs have demonstrated anti-angiogenic effects when given in frequent, smaller doses.

Folkman envisions that someday angiogenesis inhibitors will be used with each other, or with other anti-cancer therapies such as low dose, metronomic chemotherapy, radiotherapy, immunotherapy, gene therapy, vaccine therapy, or others.

With 50 or more angiogenesis inhibitors in clinical trials, promising results are now beginning to emerge. Still in Phase II trials, endostatin and angiostatin have led to long-term disease stabilization and improved quality of life in many patients, with a return of strength, weight, and hair growth--and virtually no toxicity. Doses are still being escalated in the trials to find the optimal regimen.

One of the most promising angiogenesis inhibitors is Avastin (bevacizumab), a monoclonal antibody against vascular endothelial growth factor (VEGF). In June 2003, Avastin was reported to prolong median survival in advanced colon cancer from 15.6 to 20.3 months when compared with standard chemotherapy alone; in July 2003, Avastin alone was reported to prolong time to disease progression in metastatic kidney cancer. In February 2004, Avastin was approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer in conjunction with standard chemotherapy.

Among other recent findings:

• In July 2003, researchers at Cornell University reported that celecoxib, an anti-inflammatory drug with anti-angiogenic effects, enhanced the response to standard chemotherapy agents in early-stage non-small-cell lung cancer.


• In May 2004, the first complete Phase III clinical trial results for thalidomide?were presented at the American Society of Clinical Oncology annual meeting.? They show an 80% response rate in patients newly diagnosed with multiple myeloma when thalidomide is added to dexamethasone, as compared with 53% with dexamethasone alone. A dozen Phase III trials are continuing around the world, with one third to one half of multiple myeloma patients responding. Australia was the first country to approve thalidomide for multiple myeloma, in December 2003.?