Tumor angiogenesis: past, present and the near future

The concept of treating solid tumors by inhibiting tumor angiogenesis was f irst articulated almost 30 Sears ago. For the next 10 years it attracted li ttle scientific interest. This situation changed, relatively slowly, over t he succeeding decade with the discovery of the first pro-angiogenic molecul es such as basic fibroblast growth factor and vascular endothelial growth f actor (VEGF), and the development of methods of successfully growing vascul ar endothelial cells in culture as well as in,vivo assays of angiogenesis. However, the 1990s have witnessed a striking change in both attitude and in terest in tumor angiogenesis and anti-angiogenic drug development, to the p oint where a remarkably diverse group of over 24 such drugs is currently un dergoing evaluation in phase I, II or III clinical trials. In this review I will discuss the many reasons for this. These features, together with othe r recent discoveries have created intense interest in initiating and expand ing anti-angiogenic drug discovery programs in both academia and industry, and the testing of such newly developed drugs, either alone, or in various combinations with conventional cytotoxic therapeutics. However, significant problems remain in the clinical application of angiogenesis inhibitors suc h as the need for surrogate markers to monitor the effects of such drugs wh en they do not cause tumor regressions, and the design of clinical trials. Also of concern is that the expected need to use anti-angiogenic drugs chro nically will lead to delayed toxic side effects in humans, which do not app ear in rodents, especially in short-term studies.