Research Article Summary
BIOL 501-Senior Project
Author, Title,
Journal, Year,
Volume, Pages
D’Amato, Robert J., Loughnan, Michael S., Flynn, Evelyn, Folkman, Judah
Thalidomide is an inhibitor of angiogenesis
Proc. Natl. Acad. Sci. USA, 1994, Vol. 91, pp. 4082-4085
Key Terms
Introduction/
Purpose
Inhibitor of Angiogenesis
Research
Materials & Methods
Question/Hypothesis
- Thalidomide is a
potent teratogen.
Hypothesis:
Thalidomide has a
direct effect on the
- Limb defects seen growing vasculature.
with thalidomide
were secondary to
an inhibition of
blood vessel
growth in the
developing fetal
limb bud.
-
- The limb bud is
unique in requiring
a complex
interaction of both
angiogenesis and
vasculogenesis
during
development.
-
- Angiogenesis is
the formation of
new blood vessels
from sprouts of
Corneal
neovascularization was
induced by an
implanted pellet of poly
(hydroxyethylmethacry
late) containing 650ng
of the potent
angiogenic protein
basic fibroblast growth
factor (bFGF) bound to
sucralfate.
Sucralfate protects the
bFGF from degradation
and provides for its
slow release, thus
producing consistent
aggressive angiogenesis
that is more
pronounced.
- Angiogenic response was
not altered by severe immune
suppression with total body
irradiation, and pellets with
Results
- Neither
thalidomide nor
EM-12, a related
teratogenic analog
(15), exhibited any
inhibitory activity
on blood vessel
growth. This result
was expected as it
has been proposed
that thalidomide
must be
metabolized by the
liver to form an
epoxide that may
be the active
teratogenic
metabolite (16).
- Thalidomide has
immunosuppressive
properties that
might have
indirectly affected
angiogenesis.
Conclusion/Discussion
- Orally administered
thalidomide is an inhibitor of
angiogenesis induced by
bFGF in the rabbit cornea
micropocket assay.
- The mechanism by which
thalidomide inhibits
angiogenesis is unknown.
- Thalidomide has shown no
effect on bFGF-induced
proliferation of endothelial
cells in culture.
- TNF-a is only weakly
angiogenic in vivo. It acts by
inducing secondary
inflammation in contrast to
bFGF, which stimulates
angiogenesis without
inflammation.
- Thus, the ability of
thalidomide to inhibit
Research Article Summary
BIOL 501-Senior Project
preexisting vessels.
- Vasculogenesis is
the formation of a
capillary bed from
endothelial cells
that have
differentiated from
mesenchymal
precursors.”
sucralfate alone did not
induce angiogenesis (data not
shown). The new vessels are
primarily induced by the
bFGF.
Recently,
angiogenesis induced by
thalidomide has
pharmacologic doses of bFGF
been used for its
supports the hypothesis that
immunosuppressive thalidomide directly inhibits
properties in the
an essential component of
treatment of
angiogenesis and does not
leproma reactions
operate through effects on
(19) and chronic
TNF-a production.
graft versus host
disease (18, 20-23). - In conclusion, thalidomide is
a potent angiogenesis inhibitor
The teratogenic
in vivo.
analog EM-12,
which shares the
- Evaluation of thalidomide
other properties of
analogs demonstrated a
thalidomide, was
correlation between
also inhibitory,
teratogenicity and
with a median
antiangiogenic potential.
inhibition of 42%.
- There are clear implications
- Supidimide, a
for the use of this drug in the
non-teratogenic
treatment of pathologic
analog that retains
angiogenesis that occurs in
the sedative
diabetic retinopathy, macular
properties of
degeneration, and solid
thalidomide,
tumors.
exhibited no
activity.
- Other analogs,
PGA and PG acid,
displayed weaker
inhibitory effects
Research Article Summary
BIOL 501-Senior Project
than thalidomide.
- The corneal
neovascularization from
thalidomide-treated
rabbits appeared more
immature than that
observed in control
animals with poorly
formed cell junctions,
incomplete basement
membrane, and fewer
associated pericytes.
Unknown Vocabulary: corneal neovascularization, chorioallantoic, sucralfate, limbus, *Supidimide, leukocytopenia, superior rectus,
epoxide, *EM-12, phthaloylglutamic anhydride (PGA), phthaloylglutamic acid (PG acid), avascular zones, carboxymethylcellulose,
fenestrations, cellular hypoxic,
Thalidomide induces limb defects by inhibiting angiogenesis during the critical point of limb and organ development in gestation
(Robert J. D'Amato, 1994).
It is proposed that thalidomide induces limb defects by inhibiting blood vessel growth in the developing fetal limb bud (Robert J.
D'Amato, 1994).
The limb bud is unique in requiring a complex interaction of both angiogenesis and vasculogenesis during development.
Angiogenesis is the formation of new blood vessels from sprouts of preexisting vessels. Vasculogenesis is the formation of a capillary
bed from endothelial cells that have differentiated from mesenchymal precursors (Robert J. D'Amato, 1994).
Thalidomide can be beneficial for anti-cancer medications due to its anti-angiogenetic effects. Drugs with anti-angiogenetic effects
can be used as anti-cancer medications (Robert J. D'Amato, 1994).