Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A

Article (PDF Available)inProceedings of the National Academy of Sciences 91(9):4082-5 · May 1994with64 Reads
DOI: 10.1097/00006982-199616030-00022 · Source: PubMed
Abstract
Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
Proc.
Nati.
Acad.
Sci.
USA
Vol.
91,
pp.
4082-4085,
April
1994
Medical
Sciences
Thalidomide
is
an
inhibitor
of
angiogenesis
(fibroblast
growth
factor/rabbit
cornea)
ROBERT
J.
D'AMATO*,
MICHAEL
S.
LOUGHNAN,
EVELYN
FLYNN,
AND
JUDAH
FOLKMAN
Department
of
Surgery,
Children's
Hospital,
Harvard
Medical
School,
Boston,
MA
02115
Communicated
by
John
A.
Glomset,
January
3,
1994
ABSTRACT
Thalidomide
is
a
potent
teratogen
causing
dysmelia
(stunted
limb
growth)
in
humans.
We
have
demon-
strated
that
orally
administered
thalidomide
is
an
inhibitor
of
aniogenesis
induced
by
basic
fibroblast
growth
factor
in
a
rabbit
cornea
micropocket
assay.
Experiments
including
the
analysis
of
thalidomide
analogs
revealed
that
the
antanio-
genic
activity
correlated
with
the
teratogenicity
but
not
with
the
sedative
or
the
mild
immunosuppressive
properties
of
tha-
lidomide.
Electron
microscopic
examination
of
the
corneal
neovascularization
of
thafidomide-treated
rabbits
revealed
spe-
cific
ultrastructural
changes
similar
to
those
seen
in
the
de-
formed
limb
bud
vasculature
of
thalidomide-treated
embryos.
These
experiments
shed
light
on
the
mechanism
of
tha-
lidomide's
teratogenicity
and
hold
promise
for
the
potential
use
of
thalidomide
as
an
orally
adminsered
drug
for
the
treatment
of
many
diverse
dease
dependent
on
angiogenesis.
Thalidomide
is
a
potent
teratogen.
It
was
developed
by
Chemie
Grunenthal
in
the
1950s
as
a
sedative
that
appeared
so
nontoxic
in
rodent
models
that
a
LD50
could
not
be
established.
In
1961,
McBride
(1)
and
Lenz
(2)
described
the
association
between
limb
defects
in
babies
and
maternal
thalidomide
usage.
Although
humans
are
exquisitely
sensi-
tive
to
the
teratogenic
effects
of
thalidomide,
experiments
in
rodents
failed
to
reveal
similar
effects
(3,
4).
Teratogenic
effects
could
be
experimentally
reproduced
by
the
adminis-
tration
of
thalidomide
to
pregnant
rabbits
at
an
oral
dose
of
100-300
mg
per
kg
per
day
(5,
6).
Over
the
past
30
years,
the
mechanism
of
thalidomide's
teratogenicity
has
been
exten-
sively
studied
but
has
remained
unsolved
(7).
We
now
postulate
that
the
limb
defects
seen
with
thali-
domide
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
angiogen-
esis
and
vasculogenesis
during
development
(8).
Vasculo-
genesis
is
the
formation
of
a
capillary
bed
from
endothelial
cells
that
have
differentiated
from
mesenchymal
precursors.
Angiogenesis
is
the
formation
of
new
blood
vessels
from
sprouts
of
preexisting
vessels.
Therefore,
the
limb
bud
would
be
a
particularly
vulnerable
target
to
a
teratogen
that
inhib-
ited
endothelial
cell
function.
We
chose
to
examine
the
effect
of
thalidomide
on
growing
vasculature
in
the
chicken
chori-
oallantoic
membrane
and
in
the
rabbit
cornea.
MATERIALS
AND
METHODS
Chicken
chorioallantoic
membrane
(CAM)
assays
were
per-
formed
as
described
(9,
10)
and
the
effects
on
the
developing
vasculature
were
recorded
at
48
h
after
implantation
of
the
0.5%
carboxymethylcellulose
pellet
containing
various
drugs.
Corneal
neovascularization
was
induced
by
an
im-
planted
pellet
of
poly(hydroxyethyl
methacrylate)
(Hydron;
Interferon
Sciences,
New
Brunswick,
NJ)
containing
650
ng
of
the
potent
angiogenic
protein
basic
fibroblast
growth
factor
(bFGF)
bound
to
sucralfate
(sucrose
aluminum
sulfate;
Bukh
Meditec,
Copenhagen)
(11).
The
addition
of
sucralfate
to
the
pellet
protects
the
bFGF
from
degradation
(12)
and
provides
for
its
slow
release,
thus
producing
consistent
aggressive
angiogenesis
that
is
more
pronounced
than
that
induced
by
bFGF/Hydron
alone.
Release
of
bFGF
from
pellets
contain-
ing
sucralfate/Hydron
could
be
detected
in
vitro
for
up
to
4
days
after
the
pellets
were
formed
compared
to
just
1
day
for
pellets
with
Hydron
alone
(11).
Pellets
were
made
by
mixing
110
pI
of
saline
containing
12
Mg
of
recombinant
bFGF
(Takeda,
Osaka)
with
40
mg
of
sucralfate;
this
suspension
was
added
to
80
pI
of
12%
(wt/vol)
Hydron
in
ethanol.
Aliquots
(10
Al)
of
this
mixture
were
then
pipetted
onto
Teflon
pegs
and
allowed
to
dry
producing
approximately
17
pellets.
A
pellet
was
implanted
into
corneal
micropockets
of
each
eye
of
an
anesthetized
female
New
Zealand
White
rabbit,
2
mm
from
the
limbus,
followed
by
a
single
topical
application
of
erythromycin
ointment
on
the
surface
of
the
cornea.
Histologic
examination
on
consecutive
days
demon-
strated
progressive
blood
vessel
growth
into
the
cornea
toward
the
pellet
with
only
rare
inflammatory
cells
seen.
This
angiogenic
response
was
not
altered
by
severe
immune
suppression
with
total
body
irradiation,
and
pellets
with
sucralfate
alone
did
not
induce
angiogenesis
(data
not
shown).
Unlike
other
models
of
corneal
angiogenesis
that
utilize
inflammation
to
stimulate
neovascularization,
the
new
vessels
are
primarily
induced
by
the
bFGF.
The
animals
were
fed
daily
from
2
days
after
implantation
by
gastric
lavage
with
either
drug
suspended
in
0.5%
carboxymethylcellulose
or
vehicle
alone.
Thalidomide
was
purchased
from
Andrulus
Pharmaceutical
(Beltsville,
MD)
and
EM-12
and
Supidimide
were
kindly
provided
by
Grunenthal
(Stolberg,
F.R.G.).
Immunosuppressed
animals
received
total
body
radiation
of
6
Gy
for
6
min
immediately
prior
to
implantation
of
the
pellets.
This
dose
of
radiation
resulted
in
a
marked
leukocy-
topenia
with
>80%o
reduction
in
the
leukocyte
count
by
day
2
and
>90o
reduction
by
day
3,
results
that
are
consistent
with
previous
reports
(13,
14).
The
animals
were
examined
with
a
slit
lamp
every
other
day
in
a
masked
manner
by
the
same
corneal
specialist
(M.S.L.).
The
area
of
corneal
neovascularization
was
deter-
mined
by
measuring
with
a
reticule
the
vessel
length
(L)
from
the
limbus
and
the
number
of
clock
hours
(C)
of
limbus
involved.
A
formula
was
used
to
determine
the
area
of
a
circular
band
segment:
C/12
x
3.1416
[r2
-
(r
-
L)2],
where
r
=
6
mm,
the
measured
radius
of
the
rabbit
cornea.
We
have
utilized
various
mathematical
models
to
determine
the
amount
of
vascularized
cornea
and
have
found
that
this
formula
provides
the
most
accurate
approximation
of
the
area
of
the
band
of
neovascularization
that
grows
toward
the
pellet.
Only
the
uniform
contiguous
band
of
neovasculariza-
Abbreviations:
bFGF,
basic
fibroblast
growth
factor;
CAM,
chicken
chorioallantoic
membrane;
PGA,
phthaloylglutamic
anhydride;
PG
acid,
phthaloylglutamic
acid;
TNF-a,
tumor
necrosis
factor
a.
*To
whom
reprint
requests
should
be
addressed.
4082
The
publication
costs
of
this
article
were
defrayed
in
part
by
page
charge
payment.
This
article
must
therefore
be
hereby
marked
"advertisement"
in
accordance
with
18
U.S.C.
§1734
solely
to
indicate
this
fact.
Proc.
Natl.
Acad.
Sci.
USA
91
(1994)
4083
tion
adjacent
to
the
pellet
was
measured.
The
noncontiguous
neovascularization,
which
can
be
seen
superiorly,
was
not
quantified
due
to
its
irregular
shape.
These
vessels
that
often
grow
concurrently
toward
the
pellet
from
the
superior
limbus
arise
from
vessels
of
the
superior
rectus
supplying
the
limbus,
are
directly
induced
by
the
bFGF/sucralfate
pellet,
and
are
histologically
identical
to
the
inferior
limbal
vessels.
How-
ever,
it
should
be
noted
that
this
superior
neovascularization
was
commonly
seen
in
control
animals
and
was
never
seen
in
thalidomide-treated
animals.
Thus,
the
total
inhibition
of
neovascularization
is
conservatively
underestimated.
RESULTS
Our
initial
investigations
were
performed
on
the
CAM.
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).
Other
thalidomide
analogs
that
have
been
shown
to
be
teratogenic
in
rodents
(17),
including
phthaloylglutamic
an-
hydride
(PGA)
and
phthaloylglutamic
acid
(PG
acid),
were
also
analyzed
(Fig.
1).
Interestingly,
weak
antiangiogenic
activity
of
the
developing
vasculature
was
seen
with
both
PG
acid
and
PGA
when
100
jig
of
either
compound
was
placed
on
the
CAM
in
a
pellet
of
0.5%
carboxymethylcellulose.
Despite
frequent
mild
scarring,
avascular
zones
were
pro-
duced
in
15%
of
the
CAMs
with
PGA
compared
to
control
0.5%
carboxymethylcellulose
pellets
in
which
no
avascular
zones
were
seen
(data
not
shown).
Based
on
these
initial
findings,
we
decided
to
test
tha-
lidomide's
effect
on
angiogenesis
induced
by
bFGF
in
the
rabbit
corneal
micropocket
model.
Treatment
with
a
terato-
0
11
C
N
11
0
N
a
0
0
c
c
0o
N
'o
0
11
C
c
,>
,
c
11
ll,
0
/
b
0
0
0
11
0
C-OH
11
e"
OH
0
0
11
SJCN
02
N
Thalidomide
EM-12
Phthaloyl
Glutamic
Anhydride
(PGA)
Phthaloyl
Glutamic
Acid
(PG
Acid)
Supidimide
FIG.
1.
Structure
of
thalidomide
and
related
analogs.
genic
dose
(200
mg/kg)
of
thalidomide
resulted
in
an
inhibi-
tion
of
the
area
of
vascularized
cornea
that
ranged
from
30
to
51%
in
three
experiments
with
a
median
inhibition
of
36%
(Figs.
2A
and
3)
(n
=
30
eyes;
P
=
0.0001,
two-way
ANOVA
with
ranked
data).
The
inhibition
of
angiogenesis
by
tha-
lidomide
was
seen
after
only
two
doses
(Fig.
2B).
The
rabbits
did
not
demonstrate
obvious
sedation
and
there
were
no
signs
of
toxicity
or
weight
loss.
The
teratogenic
analog
EM-12,
which
shares
the
other
properties
of
thalidomide,
was
also
inhibitory,
with
a
median
inhibition
of
42%
(n
=
10
eyes;
P
=
0.002,
one-way
ANOVA
with
ranked
data).
Supidimide,
a
nonteratogenic
analog
that
retains
the
sedative
properties
of
thalidomide,
exhibited
no
activity
(area
107%
of
control;
n
=
10
eyes;
not
statistically
different
from
control).
Other
ana-
logs,
PGA
and
PG
acid,
displayed
weaker
inhibitory
effects
o
100-
N
,
80
v
Q
C.)
CZ)
-F
60-
a)
0
40
0
20-
O-
A
M
Supidimide
o
Thalidomide
El
EM12
0
Thalidomide-irradiated
==4"~
Animal
treatment
groups
N4
40
-
Pi
B
E
c
30-
N
Co
0
0a
20-
co
-a
a)
0
.:
0'-
0
2
4
6
8
10
12
Days
post-implantation
FIG.
2.
(A)
Inhibition
of
bFGF-induced
corneal
neovasculariza-
tion
by
thalidomide
and
related
analogs
expressed
as
percent
of
median
control
on
day
8.
Pellets
containing
bFGF
and
sucralfate
were
implanted
into
micropockets
of
both
corneas
of
rabbits
(18).
Vessel
ingrowth
into
the
clear
cornea
from
the
limbus
was
first
noted
on
day
2
and
treatments
(200
mg/kg
orally)
were
begun
on
this
day.
The
area
of
corneal
neovascularization
was
measured
from
day
4
through
day
12.
Day
8
measurements
were
used
for
comparison
between
groups.
No
regression
of
vessels
and
near
maximal
neovas-
cularization
was
seen
at
this
time
point.
Statistical
analysis
was
performed
with
ANOVA
with
ranked
data
to
account
for
interex-
perimental
variation
and
to
guard
against
a
nonnormal
distribution
of
data
(i.e.,
outliers)
by
utilizing
a
nonparametric
method.
(b)
Time
course
of
inhibition
of
neovascularization
with
thalidomide.
Mean
areas
of
corneal
neovascularization
with
standard
error
bars
are
presented
from
one
experiment
that
is
representative
of
the
three
experiments
performed
with
thalidomide
on
nonirradiated
animals.
Data
presented
from
the
first
time
point
after
administration
of
the
drug
through
the
completion
of
the
study
are
statistically
different
(n
=
10
eyes;
P
<
0.005
for
all
time
points,
one-way
ANOVA
with
ranked
data).
Medical
Sciences:
D'Amato
et
al.
4084
Medical
Sciences:
D'Amato
et
al.
than
thalidomide
(data
not
shown).
The
density
of
vessel
ingrowth
in
thalidomide-treated
animals
was
also
markedly
reduced.
Due
to
the
lack
of
an
objective
grading
scale,
these
results
are
not
presented.
Thalidomide
has
immunosuppressive
properties
that
might
have
indirectly
affected
angiogenesis.
Recently,
thalidomide
has
been
used
for
its
immunosuppressive
properties
in
the
treatment
of
leproma
reactions
(19)
and
chronic
graft
versus
host
disease
(18,
20-23).
However,
in
humans
its
immuno-
suppressive
properties
are
weak
and
delayed
with
little
effect
in
acute
graft
versus
host
disease
(24).
Because
the
effect
of
thalidomide
on
the
immune
system
is
similar
but
weaker
than
that
of
cyclosporin
A
(25),
we
tested
cyclosporin
A
at
the
highest
tolerated
dose
of
25
mg/kg.
No
statistically
signifi-
cant
effect
was
observed
compared
to
control.
To
investigate
.I]
Proc.
Natl.
Acad.
Sci.
USA
91
(1994)
further
the
immune
interactions,
we
pretreated
the
rabbits
with
the
maximally
tolerated
immunosuppressive
dose
of
total
body
irradiation.
Immunosuppressed
animals
re-
sponded
equally
well
to
thalidomide,
with
a
median
inhibition
of
neovascularization
of
52%
(n
=
12;
P
=
0.0001,
one-way
ANOVA
with
ranked
data)
as
compared
to
irradiated
place-
bo-treated
controls
(Fig.
2A).
Electron
microscopic
examination
of
corneas
from
tha-
lidomide-treated
and
control
animals
revealed
ultrastructural
differences.
Vessels
in
the
thalidomide-treated
group
dem-
A
ti½*
A4-
B
*L
FIG.
3.
Representative
corneas
at
8
days
after
implantation
of
bFGF
pellets
from
control
(A)
and
thalidomide-treated
(B)
rabbits.
There
is
prominent
corneal
neovascularization
(arrows)
in
the
con-
trol
with
associated
corneal
clouding,
which
was
demonstrated
histologically
to
be
stromal
edema
without
inflammation.
The
tha-
lidomide-treated
animal
has
markedly
less
neovascularization
with
minimal
corneal
edema.
FIG.
4.
Electron
micrographs
of
corneal
neovascularization
ob-
served
in
a
thalidomide-treated
rabbit
10
days
after
implntation
of
a
pellet
containing
bFGF.
(A)
High-magnification
(x40,000)
view
of
typical
fenestrations
(arrow)
in
an
endothelial
cell
from
corneal
neovascularization
in
thalidomide-treated
rabbit.
(B)
High-
magnification
(x60,000)
view
of
an
area
of
cell
thinning
(asterisk)
adjacent
to
a
cell
junction
in
thalidomide-treated
corneal
neovascu-
larization.
These
changes
were
not
seen
in
control
day
10
corneal
neovascularization.
(Bars
=
0.1
amn.)
Ai
.:!
:fsi,
f.....
;7
.1
-.
.;z
ebi,
r,4
'O
"
'o
..
I.-
1
'4
"
",::,
Proc.
Natl.
Acad.
Sci.
USA
91
(1994)
4085
onstrated
fenestrations
not
seen
in
control
animals
(Fig.
4A).
Fenestrations
have
been
previously
reported
to
be
specific
to
regressing
corneal
blood
vessels
after
removal
of
the
angio-
genic
stimulus
(26).
However,
in
that
model,
endothelial
cell
regression
was
associated
with
platelet
plugging
and
cellular
hypoxic
changes
such
as
swollen
mitochondria,
which
were
not
seen
in
the
thalidomide-treated
animals.
Interestingly,
histologic
changes
previously
described
in
the
vasculature
of
the
limb
buds
from
chicken
embryos
treated
with
thalidomide
(27)
were
also
seen
in
the
corneal
neovascularization
of
our
thalidomide-treated
rabbits
including
vesicular
projections
into
the
lumen
and
extreme
thinning
of
cell
processes
(Fig.
4B).
In
general,
the
corneal
neovascularization
from
thali-
domide-treated
rabbits
appeared
more
immature
than
that
observed
in
control
animals
with
poorly
formed
cell
junc-
tions,
incomplete
basement
membrane,
and
fewer
associated
pericytes.
These
findings
support
the
hypothesis
that
tha-
lidomide
has
a
direct
effect
on
the
growing
vasculature.
DISCUSSION
Orally
administered
thalidomide
is
an
inhibitor
of
angiogen-
esis
induced
by
bFGF
in
the
rabbit
cornea
micropocket
assay.
The
mechanism
by
which
thalidomide
inhibits
angio-
genesis
is
unknown.
Thalidomide
has
shown
no
effect
on
bFGF-induced
proliferation
of
endothelial
cells
in
culture
(data
not
shown).
Current
studies
are
focused
on
the
identi-
fication
of
the
most
active
thalidomide
metabolite.
The
formation
of
an
active
metabolite
by
the
liver
in
vivo
provides
an
explanation
of
the
observation
that
the
effect
of
tha-
lidomide
on
growing
vessels
is
seen
only
when
given
sys-
temically.
Thalidomide
has
been
shown
to
suppress
tumor
necrosis
factor
a
(TNF-a)
production
from
macrophages
(28).
How-
ever,
macrophages
were
rarely
seen
in
histologic
examina-
tions
of
our
model
of
corneal
neovascularization.
Further-
more,
studies
examining
the
role
of
TNF-a
in
corneal
angio-
genesis
have
failed
to
detect
TNF-a
production
in
a
model
of
inflammatory
corneal
angiogenesis
in
which
macrophages
were
prominent
(29).
TNF-a
is
only
weakly
angiogenic
in
vivo.
It
acts
by
inducing
secondary
inflammation
in
contrast
to
bFGF,
which
stimulates
angiogenesis
without
inflamma-
tion
(30).
Thus,
the
ability
of
thalidomide
to
inhibit
angio-
genesis
induced
by
pharmacologic
doses
of
bFGF
supports
the
hypothesis
that
thalidomide
directly
inhibits
an
essential
component
of
angiogenesis
and
does
not
operate
through
effects
on
TNF-a
production.
In
conclusion,
thalidomide
is
a
potent
angiogenesis
inhib-
itor
in
vivo.
In
this
model
of
corneal
angiogenesis,
we
have
tested
many
putative
angiogenesis
inhibitors
(including
an-
timitotic
agents,
cis-retinoic
acid,
tamoxifen,
and
others).
Thalidomide
was
the
only
agent
capable
of
inhibiting
angio-
genesis
after
oral
administration.
Evaluation
of
thalidomide
analogs
demonstrated
a
correlation
between
teratogenicity
and
antiangiogenic
potential.
The
weak
and
delayed
immu-
nosuppressive
action
of
thalidomide
when
used
clinically,
its
inhibition
of
angiogenesis
in
radiation-immunosuppressed
animals,
and
the
lack
of
effect
of
the
functionally
related
immunosuppressive
agent
cyclosporin
A
argue
for
a
direct
effect
of
thalidomide
on
angiogenesis.
Further
support
for
this
hypothesis
is
derived
from
the
ultrastructural
changes
seen
in
thalidomide-treated
animals.
There
are
clear
impli-
cations
for
the
use
of
this
drug
in
the
treatment
of
pathologic
angiogenesis
that
occurs
in
diabetic
retinopathy,
macular
degeneration,
and
solid
tumors.
Because
antiangiogenic
ther-
apy
is
likely
to
be
long-term,
there
is
a
need
for
an
orally
efficacious
inhibitor.
Special
thanks
to
Klio
Chatzistefanou,
Geri
Jackson,
Evelyn
Gonzalez,
Pat
D'Amore,
Helene
Sage,
Michael
O'Reilly,
Michael
Kaplan,
Tony
Adamis,
Elizabeth
N.
Allred,
Ramzi
Cotran,
and
Dianna
Ausprunk
for
their
assistance
and
advice.
We
also
thank
E.
Frankus
and
K.
Zwingenberger
of
Grunenthal
GMBH
for
providing
technical
information,
EM-12,
and
supidimide.
R.J.D.
is
a
Howard
Hughes
Medical
Institute
physician
research
fellow.
M.S.L.
is
partly
supported
by
the
Ruth
Rae
Davidson
corneal
fellowship
endowment.
Animal
studies
were
reviewed
and
approved
by
the
animal
care
and
use
committee
of
Children's
Hospital
and
are
in
accordance
with
the
guidelines
of
the
Department
of
Health
and
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Medical
Sciences:
D'Amato
et
al.
    • "Thalidomide possesses anti-angiogenic actions in the rabbit corneal micropocket assay [10], the rat aortic ring assay (in the presence of human liver microsomes), and in in vitro cultures of human umbilical vein endothelial cells (HUVECs), [6,[11][12][13][14][15]. This action has been linked to the damage to embryos following thalidomide exposure [3, 6, 8, 10]. Thalidomide also possesses immunomodulatory characteristics [16, 17]. "
    [Show abstract] [Hide abstract] ABSTRACT: Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.
    Full-text · Article · May 2016
    • "Recently, the anti-IL-6 receptor antibody tocilizumab decreased serum levels of VEGF [39]. Thalidomide, currently used in multiple myeloma treatment but also tried in lupus and RA, is a potent TNF-α antagonist and angiogenesis inhibitor [27,40]. Thalidomide could suppress both synovitis and angiogenesis [27], suggesting that its antiangiogenic effects may be, in part, VEGF-independent. "
    [Show abstract] [Hide abstract] ABSTRACT: Haemophilia is an inherited bleeding disorder that can lead to degenerative joint arthropathy due to recurrent bleeding episodes affecting the musculoskeletal system of the patient. The cause of bleeding can be either traumatic or spontaneous. The pathogenesis of haemophilic arthropathy is unclear as many factors like iron, inflammatory cytokines, and angiogenic factors contribute to this process. Blood into joints can deteriorate the bone to such an extent that the patient experiences pain, reduction of the range of movement, and deformity of the joint, conditions that could have a great impact on quality of life. Over the years, management of haemophilic arthropathy has changed. Nowadays, early diagnosis with high resolution imaging like magnetic resonance imaging along with application of prophylaxis regimens can reduce the extent of damage to the joints. However, not all haemophilia patients have access to these interventions as cost may be prohibitive for some of them. The need for new, easy, and cost-effective strategies with the ability to identify early changes could be beneficial and could make a difference in the management of haemophilic arthropathy. Understanding the mechanism of processes like angiogenesis in the mechanism of developing arthropathy could be innovative for these patients and could help in the detection of new early diagnostic and therapeutic markers.
    Article · May 2016
    • "Thalidomide is a kind of glutamate derivatives. In the late of last century, people found that thalidomide can inhibit angiogenesis by blocking bFGF and VEGF, and it can also modulate the immune system by co-stimulating T cell proliferation [12][13][14]. In recent years, some study found that thalidomide can induce the apoptosis of tumor cells and some found it can improve the weight in cancer patients with cachexia [15, 16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab (R-CHOP) is the standard treatment for patients with diffuse large B cell lymphoma (DLBCL). However, rituximab cannot be popularly applied in a considerable number of patients with DLBCL because of economic reasons. To develop a new regimen to improve the outcome of these patients is extremely important. In our study, sixty five patients with DLBCL were randomly assigned to thalidomide plus CHOP group (n=32) or to CHOP alone group (n=33). Objective response rates (ORR) and complete remission rates (CRR) were 96.7% and 80.6% in T-CHOP group versus 78.9 % and 57.8 % in CHOP group, respectively (P <0.05). At a median follow-up of 96 months, median PFS for T-CHOP group was still not reached yet, and in CHOP group it was 22.9 months (95% CI [0-50.4]). (P=0.163). Median overall survival (OS) for T-CHOP group was also not reached, and the estimated median OS for CHOP group was 83.5 months, the difference of OS between the two groups is not significant (p=0.263). But, in patients with Bcl-2 positive and Bcl-6 negative, the median PFS in T-CHOP group was longer than that in CHOP group (111.0 vs 8.5 months (P=0.017). In addition, thalidomide did not significantly increase the grade 3/4 toxicity of CHOP. We concluded that the addition of thalidomide to the CHOP regimen significantly improved the CRR and showed a trend of improving clinical outcome in patients with DLBCL, especially for patients with Bcl-2 positive and Bcl-6 negative B-cell phenotype, without increased toxicity.
    Article · Apr 2016
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