The life of Judah Folkman took an unexpected turn one morning in May 1998. That day, a front-page article in the New York Times announced that Folkman, a professor at the Harvard Medical School in Boston, had discovered two natural compounds, angiostatin and endostatin, that dramatically shrunk tumors in mice by cutting the cancer¿s blood supply. Along the story was a quote from Nobel laureate James Watson: "Judah is going to cure cancer in two years." Watson eventually backed off, but the media frenzy had already exploded worldwide, transforming Folkman into a reluctant hero in the fight against cancer.

Folkman's reputation in the medical world was well established long before he hit the headlines. The son of a rabbi, he was a student when he developed the first implantable atrio-ventricular pacemaker in the 1950s. Later, he pioneered the first implantable polymers to obtain slow drug releasing. At the age of 34, when he became the youngest professor of surgery to be hired at the Harvard Medical School, he was already studying ways to block the formation of new blood vessels--a process called angiogenesis--to stop tumor growth. His ideas, initially met with skepticism by oncologists, are today the basis for an area of research that is attracting enormous interest. At least 20 compounds with an effect on angiogenesis are now being tested in humans for a range of pathologies that include cancer, heart disease and vision loss [see "Keep Both Eyes on the Blockers"]. But the premature hype continues to generate disproportioned hopes among the press, the public and the stock market. Recently, we met Folkman in his laboratory at the Children¿s Hospital in Boston to ask about his work and the progress of clinical trials on endostatin and angiostatin.--Sergio Pistoi and Chiara Palmerini

What makes anti-angiogenesis drugs a promising strategy in cancer therapies?

Many experiments showed that tumor growth and metastasis are angiogenesis-dependent. Tumors cannot grow unless they recruit their own private blood supply. That is why microvascular endothelial cells [the cells lining capillaries], which are essential for new blood vessel growth, have become an important target in cancer therapy. Antiangiogenic compounds do not attack the tumor cells directly, as chemotherapies do. Instead they turn endothelial cells off, so they won¿t make new blood vessels, and the tumor will eventually stop growing. The effect of angiostatin and endostatin is tumor-specific. So you have very few, if any, adverse effects on the organism. Targeting endothelial cells has some advantages: these cells are genetically stable, meaning that they do not mutate. In contrast, tumor cells tend to mutate and in this way they often become drug-resistant. Therefore, development of acquired drug resistance, which is common with chemotherapy, is less likely with angiogenesis inhibitors. Moreover, each endothelial cell can support up to 100 tumor cells; that means that by knocking out just few endothelial cells you have an effect on hundreds of tumor cells.

What impact did the sudden celebrity have on your daily work?

At the beginning I felt an enormous pressure. Patients were calling at all times and many flew to Boston. We hired three people just to answer the patients' and media's queries around the clock. [The news] raised expectations and demand for angiogenesis inhibitors before these drugs had completed testing in clinical trials. On the other hand, there are many patients alive today because they were treated with antiangiogenic drugs: thalidomide for multiple myeloma or low-dose interferon alpha for giant cell bone tumors or for angioblastomas. For any new type of therapy, there is always a dilemma about when to inform the public. If it¿s too early, then physicians are besieged by calls from patients for drugs that cannot be obtained. If too late, then critics say that hope was destroyed for patients with advanced disease. Our own research work was temporarily impacted because of many phone calls, but in the long run the effect was minimal.

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