Therapeutic Angiogenesis

strategy is designed to promote the development of supplemental collateral blood vessels that will act as endogenous bypass conduits
Promotion of coronary collateral growth has many attractive features, particularly in
patients with angina who are not indicated for percutaneous coronary intervention or coronary artery
bypass grafting surgery.
Two major avenues:
1. gene therapy (the introduction of new genetic material into somatic cells to synthesize proteins that are
missing, defective, or desired for specific therapeutic purposes)
2. protein-based therapy
(administration of the growth factors, instead of the genes encoding for the growth factors responsible for angiogenesis).

Delivery of angiogenic factors (Protein-based therapy with cytokines including vascular endothelial growth factor and fibroblast growth factor) demonstrated functionally significant angiogenesis in several animal models.
Delivery of gene encoding for the respective protein product has been shown to induce angiogenesis in numerous
animal models, and expression of a functioning product has been demonstrated with evidence of
neovascularization and improved perfusion in the target myocardium.

Various early clinical
trials of therapeutic angiogenesis have shown reduction in anginal symptoms and increases in exercise
time, as well as objective evidence of improved perfusion, left ventricular function and angiographic
appearance following such angiogenic treatments.

Patients with chronic critical limb ischemia
who are not candidate for surgical or percutaneous revascularization- Therapeutic angiogenesis, which has the goal to achieve the process of new
blood vessel formation via the administration of growth factors, has become a new promising hope. The
discovery of the possibility of inducing sprouting of new vessels from preexisting vasa (angiogenesis) or
the in situ differentiation of endothelial cells from stem cell precursors (vasculogenesis) have open new
lease on life. In experimental studies therapeutic angiogenesis has been produced by
recombinant growth-factor protein application as well as by growth factor gene therapy. Most widely
studied factors belong to vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF)
families. Studies have also shown that, angiogenic growth factors stimulate endothelial cell migration
and accelerate endothelial repair by enhancing post-injury re-endothelization.

Angiostatic Approach to Cancer Therapy

Various inhibitors of angiogenesis are under investigation in patients with
advanced cancer:


Drugs that block matrix breakdown:
1. Marimastat

against
pancreas,
non-small
cell lung,
breast
cancers
Synthetic inhibitor of
matrix
metalloproteinases
(MMPs)
2. Bay 12-9566

against lung,
ovary, and
pancreatic
cancers
Synthetic inhibitor of
tumor growth
3. AG3340

against
non-small
cell lung;
against
prostate
cancer
Synthetic MMP
inhibitor



4. CGS
27023A

Synthetic MMP inhibitor
5. COL-3

Synthetic MMP
inihibitor.
Tetracycline derivative
6. Neovastat

against
non-small
cell lung
cancer
Naturally occurring
MMP inhibitor
7. BMS-275291

Synthetic MMP
Inhibitor
8. Dalteparin
9. Suramin



Drugs that inhibit endothelial cells directly:

1. TNP-470

against
advanced
cancer for
adults with
solid tumors;
against
pediatric solid
tumors,
lymphomas,
and acute
leukemias
Synthetic
analogue of
fumagillin; inhibits
endothelial cell
growth
2. Thalidomide

against
Kaposi's
sarcoma,
glioblastoma,
prostate, lung,
and breast
cancers
Mech. unknown
3. Squalamine

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

Induction of
apoptosis in
proliferating
endothelial cells
5. Endostatin

solid
tumor
Inhibition of
endothelial cells

6. 2-methoxyestradiol
(2-ME)
7. CC-5013 (Thalidomide Analog)
8. LY317615 (Protein Kinase C Beta Inhibitor)
9.Soy Isoflavone (Genistein; Soy Protein Isolate)

Drugs that block activators of angiogenesis:

1. Anti-VEGF Antibody
against lung,
breast,
prostate,
colorectal, and
renal cancers
Monoclonal
antibody to
vascular
endothelial
growth factor
(VEGF)



2. SU5416

against
Kaposi's
sarcoma,
against
metastatic
colorectal
cancer, and
against
advanced
malignancies
Blocks VEGF
receptor
signaling
3. SU6668

against
advanced
tumors
Blocks VEGF,
FGF, and EGF
receptor
signaling





4. PTK787/ZK
22584

against
advanced
cancers
against
glioblastoma
and Kaposi's
sarcoma;
against Von
Hippel Lindau
disease
Blocks VEGF
receptor
signaling
5. Interferon-alpha
Commercially
Available

Inhibition of
bFGF and
VEGF
production



Drugs that inhibit endothelial-specific integrin/survival signaling:

1. Vitaxin

Antibody to
integrin present
on endothelial
cell surface
2. EMD121974

against Kaposi's
sarcoma, brain
tumors, and
solid tumors
Small molecule
blocker of integrin
present on
endothelial cell
surface

Drugs with non-specific mechanism of action:
1. CAI

against ovarian,
non-small cell
lung, and renal
cell cancers
Inhibitor of
calcium influx
2. Interleukin-12
against Kaposi's
sarcoma and
solid tumors
Up-regulation of
interferon gamma
and IP-10
3. IM862
Against AIDS-related
Kaposi's
sarcoma
Unknown
mechanism

Antiangiogenic therapy combined with conventional anticancer therapies may represent an useful tool in the future care of patients with cancer.

Process of Angiogenesis

In physiological conditions, angiogenesis occurs primarily in embryo development, during wound healing and in response to ovulation.

However, pathological angiogenesis, or the abnormal rapid proliferation of blood vessels,is implicated in over 20 diseases, including cancer, psoriasis and age-related macular degeneration.
The angiogenic sequence
A cell activated by a lack of oxygen releases angiogenic molecules that attract inflammatory and endothelial cells and promote their proliferation.

During their migration, inflammatory cells also secrete molecules that intensify the
angiogenic stimuli.

The endothelial cells that form the blood vessels respond to the angiogenic call by
differentiating and by secreting matrix metalloproteases (MMP), which digest the
blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic stimuli.

Several protein fragments produced by the digestion of the blood-vessel walls intensify the proliferative and migratory activity of endothelial cells, which then form a capillary tube by altering the arrangement of their adherence-membrane proteins.

Finally, through the process of anastomosis, the capillaries emanating from the arterioles and the venules will join, thus resulting in a continuous blood flow.

Normal regulation of angiogenesis is governed by a fine balance between factors that
induce the formation of blood vessels and those that inhibit the process.
When this balance is destroyed, it usually results in pathological angiogenesis which causes increased blood-vessel formation in diseases that depend on angiogenesis.

More than 20 endogenous positive regulators of angiogenesis have been described,
1. growth factors, can induce the division of cultured endothelial cells thus indicating a direct action on these cells.
vascular endothelial growth factor (VEGF),
transforming growth factors (TGF-beta),
fibroblast growth factors (FGF),
epidermal growth factor (EGF),
angiogenin
Other factors have virtually no effect on the division of cultured endothelial cells indicating that their angiogenic action is indirect.

2. Matrix metalloproteinases,
3.Cytokines
4. Integrins