In 1971, J Folkman published, in the New England Journal of Medicine, a hypothesis that tumor growth is angiogenesisdependent. The hypothesis predicted that tumors would be unable to grow beyond a microscopic size of 1–2mm3 without continuous recruitment of new capillary blood vessels. Folkman1 introduced the concept that tumors probably secreted diffusible molecules that could stimulate the growth of new blood vessels toward the tumor and that the resulting tumor neovascularization could conceivably be prevented or interrupted by drugs called angiogenesis inhibitors. Beginning in the 1980s, the biopharmaceutical industry began exploiting the field of antiangiogenesis for creating new therapeutic compounds for modulating new blood vessel growth in angiogenesis-dependent diseases. The antiproliferative activity of interferons (IFN) against human tumors was first demonstrated in the 1960s with partially purified IFN-a by Strander2 at the Karolinska Institute. A mixture of IFN inhibited the migration of capillary endothelial cells in vitro3 and lymphocyte-induced angiogenesis in vivo, 4 as well as tumor angiogenesis. 5 The first angiogenesis inhibitor IFN-a administered at low doses was reported in 1980. 3 Since 1988, IFN-a has been used successfully to cause complete and durable regression of life-threatening pulmonary hemangiomatosis, hemangiomas of the brain, airway and liver in infants, recurrent high-grade giant cell tumors refractory to conventional therapy and angioblastomas. 6–9 These tumors all express high levels of fibroblast growth factor-2 (FGF-2) as their major angiogenic mediator.

Cartilage has been studied as a potential source of angiogenesis inhibitor because of its avascularity. In fact, cartilage is a relatively tumor-resistant tissue and the tumor associated with cartilage, chondrosarcoma, is the last vascularized of all solid tumors. In 1980, Langer et al. 10 partially purified extracts of cartilage, which inhibited tumor-induced neovascularization when delivered regionally (via controlled release polymer) and when delivered systemically (via infusion). Ten years later, Langer and co-workers11 purified an angiogenesis inhibitor from bovine scapular cartilage and obtained amino-terminal sequence.