Make your own free website on Tripod.com

Angiogenesis Inhibitors in Cancer Research


By The National Cancer Institute

One promising avenue of cancer research is the study of a group of compounds called angiogenesis inhibitors. These are drugs that block angiogenesis, the development of new blood vessels. Solid tumors cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters) without inducing the formation of new blood vessels to supply the nutritional needs of the tumor. By blocking the development of new blood vessels, researchers are hoping to cut off the tumor's supply of oxygen and nutrients, and therefore its continued growth and spread to other parts of the body.

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 ), 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.

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 .

Angiogenesis Inhibitors in Clinical Trials

Drug

Sponsor

Trial

Mechanism

Drugs that prevent new blood vessels from invading surrounding tissue:

Marimastat

British Biotech
Annapolis, Md.

Phase III

Synthetic inhibitor of matrixmetalloproteinases (MMPs)

Bay 12-9566

Bayer
West Haven, Conn.

Phase III

Synthetic MMP inhibitor

AG3340

Agouron
LaJolla, Calif.

Phase III

Synthetic MMP inhibitor

CGS27023A

Novartis
East Hanover, N.J.

Phase I

Synthetic MMP inhibitor

COL-3

Collagenex Pharmaceuticals
Newtown, Pa.

Phase I

Antibiotic derivative that inhibits MMPs

Vitaxin

Ixsys, Inc.
LaJolla, Calif.

Phase I

Antibody to integrin, present on endothelial cell surface

Natural inhibitors of angiogenesis:

Platelet factor-4

Repligen
Cambridge, Mass.

Phase II

Inhibits endothelial cell growth

Interleukin-12

Genetics Institute
Cambridge, Mass.

Phase I/II

Inhibits endothelial cell growth

Drugs that block factors that stimulate the formation of blood vessels:

RhuMabVEGF

Genentech
South San Francisco, Calif.

Phase II/III

Monoclonal antibody to vascular endothelial growth factor (VEGF)

SU5416

Sugen, Inc.
Redwood City, Calif.

Phase I

Molecule that blocks VEGF receptor signaling

Interferon-alpha

Commercially available

Phase II/III

Inhibits release of endothelial growth factor

Targeted anti-vascular therapy:

ZD0101

Zeneca Pharmaceuticals
Wilmington, Del.

Phase I/II

Bacterial toxin that binds to new blood vessels and induces inflammatory response

Interrupts function of dividing endothelial cells:

TNP-40

TAP Pharmaceuticals, Inc.
Deerfield, Ill.

Phase II

Synthetic analogue of fungal protein;inhibits endothelial cell growth

Unknown mechanism; inhibits angiogenesis in laboratory and animal assays:

Thalidomide

Entremed, Inc.
Rockville, Md.

Phase II

Synthetic sedative: Unknown mechanism

CAI

National Cancer Institute
Bethesda, Md.

Phase I/II

Non-specific inhibitor cell invasion and motility

Squalamine

Magainin Pharmaceuticals, Inc.
Plymouth Meeting, Pa.

Phase I

Extract from dogfish shark liver; inhibits sodium-hydrogen exchanger, NHE3

Suramin

Parke-Davis
Morris Plains, N.J.

Phase II/III

Non-specific multi-site effects

IM862

Cytran
Kirkland, Wash.

Phase II

Unknown mechanism

 

The National Cancer Institute of The National Institutes of Health. Press Release: Angiogenesis Inhi The National Cancer Institute