Current Status of Angiogenesis Inhibitors
Four years ago, the first clinical trials on angiogenesis inhibitors began with a great deal of hype and enthusiasm. Angiogenesis inhibitors were widely heralded as being the long sought "miracle cure" in the treatment of cancer. However, Dr. Judah Folkman, the prime mover in the development of the drugs, remained cautious. He was fully aware of the history of new cancer treatments that produced remarkable effects in laboratory animals, only to be disappointing when tested in humans. As results of the first clinical trials began to come in, this caution appeared to be warranted, as some trials produced the expected results, while others were disappointing. 4 5This report provides an update on background information that I described earlier, and indicates some of the emerging roles of angiogenesis inhibitors in cancer therapy.
Why are angiogenesis inhibitors important?
Angiogenesis refers to the formation of new blood vessels, an absolutely essential process for tumors to grow and spread. 1The endothelial cells that form the walls of blood vessels are the source of new blood vessels. Although in normal tissues new blood vessel formation is a process that is closely controlled by various activators and inhibitors of angiogenesis, in tumors activation is dominant. The activation of oncogenes (cancer causing genes) during tumor formation results in the formation of proteins that promote angiogenesis, and the down regulation of angiogenesis suppressor proteins.
How is angiogenesis inhibitor therapy different from other cancer therapies?
It is important to distinguish between direct and indirect classes of angiogenesis inhibitors.3 Direct inhibitors of angiogenesis, such as angiostatin and endostatin, prevent vascular endothelial cells from proliferating, migrating, or avoiding cell death in response to stimuli from pro-angiogenic proteins. Direct inhibitors are the least likely to acquire drug resistance, since they target genetically stable endothelial cells rather than unstable mutating tumor cells. Indirect inhibitors prevent the expression of or block the activity of tumor proteins that activate angiogenesis, or block the expression of its receptor on endothelial cells. Examples of these tumor proteins are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor.
It can be difficult to assess the effectiveness of angiogenesis inhibitors, since they often do not shrink tumors like other therapies. Their function is to stop further tumor growth, but the tumor can remain in a dormant state. A search for suitable markers for this purpose is in progress.
What are the emerging applications of angiogenesis inhibitors for cancer treatments?
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