Content area
Full Text
REVIEWS
DISCOVERY AND DEVELOPMENT OF BEVACIZUMAB, AN ANTI-VEGF ANTIBODY FOR TREATING CANCER
Napoleone Ferrara*, Kenneth J. Hillan,Hans-Peter Gerber* and William Novotny
The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.
ENDOTHELIAL CELLS
The main type of cell in the inside lining of blood vessels, lymph vessels and the heart.
The observation that tumour growth can be accompanied by increased vascularity was reported more than a century ago (for a review, see REF. 1). However, it was
not until 1939 that Ide and colleagues first postulated the existence of a tumour-derived blood-vessel-growth stimulating factor that might serve to provide a neovascular supply to the growing tumour2.A few years later, Algire et al. proposed that the rapid growth of tumour transplants is dependent upon the development of a rich vascular supply, on the basis of the observation that local increases in blood-vessel density precede rapid tumour growth3. The field was then quiet until the 1960s, when experiments by Greenblatt and Shubik4,
and Ehrmann and Knoth5,provided early evidence that tumour angiogenesis was mediated by diffusible factors produced by tumour cells.
In 1971, Folkman proposed that anti-angiogenesis might be an effective anticancer strategy6. On the basis of this pioneering hypothesis, Folkman and collaborators initiated efforts aimed at the isolation of a tumour angiogenesis factor from human and animal tumours in the early 1970s7.In 1978, Gullino also suggested
that blocking angiogenesis could prevent cancer8.
Subsequently, the angiogenic effects of a variety of factors (for example, epidermal...