About 20 angiogenesis inhibitors are currently being tested in human trials. Most are in early phase I or II clinical (human) studies. Three are in phase III testing and the results for one are expected by the end of 1999. (See list of Angiogenesis Inhibitors in Clinical Trials.) Phase I/II trials include a limited number of people to determine the safety, dosage, effectiveness, and side effects of a drug. In phase III trials, hundreds of people around the country are assigned at random to receive either the new treatment or the standard treatment.

Background

In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.

Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E₁ and E₂, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and ß), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).

At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.

Strategies

Of the anti-angiogenesis drugs now in clinical trials, some were designed to target specific molecules involved in new blood vessel formation. For others, the exact mechanism of the drug is not known, but it has been shown to be anti-angiogenic by specific laboratory tests (in the test tube or in animals).

In general, four strategies are being used by investigators to design anti-angiogenesis agents:

• Block the factors that stimulate the formation of blood vessels

• Use natural inhibitors of angiogenesis

• Block molecules that allow newly forming blood vessels to invade surrounding tissue

• Incapacitate newly dividing endothelial cells

Standard Chemotherapy Versus Angiogenesis Inhibitors

Several differences between standard chemotherapy and anti-angiogenesis therapy result from the fact that angiogenesis inhibitors target dividing endothelial cells rather than tumor cells. Anti-angiogenic drugs are not likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss -- symptoms characteristic of standard chemotherapy treatments. Also, since anti-angiogenic drugs may not necessarily kill tumors, but rather hold them in check indefinitely, the endpoint of early clinical trials may be different than for standard therapies. Rather than looking only for tumor response, it may be appropriate to evaluate increases in survival and/or time to disease progression.

Drug resistance is a major problem with chemotherapy agents. This is because most cancer cells are genetically unstable, are more prone to mutations and are therefore likely to produce drug resistant cells. Since angiogenic drugs target normal endothelial cells which are not genetically unstable, drug resistance may not develop. So far, resistance has not been a major problem in long-term animal studies or in clinical trials.

Finally, anti-angiogenic therapy may prove useful in combination with therapy directly aimed at tumor cells. Because each therapy is aimed at a different cellular target, the hope is that the combination will prove more effective. Early trials are under way.

See list of Angiogenesis Inhibitors in Clinical Trials.

For further information about clinical trials, refer to the National Cancer Institute's website: http://cancertrials.nci.nih.gov.

For more information about cancer visit NCI's website for patients, public and the mass media at http://rex.nci.nih.gov or NCI's main website at http://www.nci.nih.gov.