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Angiogenesis Inhibitors in Cancer Research
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 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:
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
The National Cancer Institute of The National Institutes of Health.
Press Release: Angiogenesis Inhi The National Cancer Institute |
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