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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. 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.
See table of angiogenesis inhibitors in
clinical trials
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-a, vascular endothelial growth factor
(VEGF), and
granulocyte colony-stimulating factor. Some
of the known
inhibitors of angiogenesis include
angiostatin, endostatin,
interferons, interleukin 1 (a and b ),
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
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-a, vascular endothelial growth factor
(VEGF), and
granulocyte colony-stimulating factor. Some
of the known
inhibitors of angiogenesis include
angiostatin, endostatin,
interferons, interleukin 1 (a and b ),
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.
Drugs that prevent new blood vessels from invading
surrounding tissue:
Drug
Sponsor
Trial
Mechanism
Marimastat
British Biotech;
Annapolis, Md.
Phase III
against
pancreas,
lung,
gastric,
breast
cancers
and glioma
Synthetic
inhibitor of
matrixmetalloproteinases
(MMPs)
Bay 12-9566
Bayer; West
Haven, Conn.
Phase III
against
lung and
prostate
cancers
Synthetic MMP
inhibitor
AG3340
Agouron;
LaJolla, Calif.
Phase III
against
lung and
prostate
cancers
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:
Drug
Sponsor
Trial
Mechanism
Platelet factor-4
Repligen Clinical
Partners;
Cambridge,
Mass.
Phase II against
Kaposi's
sarcoma, renal
melanoma, and
colon
carcinoma
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:
Drug
Sponsor
Trials
Mechanism
RhuMabVEGF
Genentech;
South San
Francisco, Calif.
Phase II/III*
against lung,
breast,
prostate,
colorectal
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
* The company has a patient hotline for these
trials: 650.225.5300
Targeted anti-vascular therapy:
Drug
Sponsor
Trial
Mechanism
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:
Drug
Sponsor
Trial
Mechanism
TNP-470
TAP
Pharmaceuticals,
Inc.; Deerfield,
Ill.
Phase I against
pediatric
cancers; Phase I
against
advanced
cancer for adults
with solid
tumors
Synthetic
analogue of
fungal
protein;
inhibits
endothelial cell
growth
Unknown mechanism; inhibits angiogenesis in
laboratory and
animal assays:
Drug
Sponsor
Trial
Mechanism
Thalidomide
Entremed, Inc.;
Rockville, Md.
Phase II against
Kaposi's sarcoma,
breast, prostate and
primary brain
cancers
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 against
hormone-refractory
prostate cancer
Non-specific
multi-site effects
IM862
Cytran;
Kirkland, Wash.
Phase II against
Kaposi's Sarcoma
Unknown
mechanism
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