Natalie De St Jeor
Biology 1615
November 11, 2012
Thiabendazole the antifungal drug is a vascular disrupting
agent.
Edward M. Marcotte, John B. Wallingford, Andrew D. Ellington, Paul E. Mead,
Michelle Byrom, Hye Ji Cha.
Abs
tra
ct
Studies on diverse organisms reveal that genes in yeast can be used in
vertebrates to control artery and vain growth. Molecules target yeast pathways and
act as angiogenesis inhibitors appropriate for chemotherapy. all of this research led
to the discov
ery that thiabendazole
(antifungal drug
that has been used for fourty
years) strongly inhibits angiogenesis in the anima
l models and human cells.
new
research, thiabendazol undoes newly established blood vessels, making it a vascular
disrupting agent. Thi
abendazole decreases vascular density and slows tumor
growth in preclinical fivrosarcome xenografts. Evolutionary repu
rposing of gene
networks has guided us
directly to the identification of a
possible
new therapeutic
application for a
cheap
drug that is
already approved for
humans.
Introduction
Yeast cells and
the
vertebrate blood vessels wou
ld not appear
to have much
in common. But
, they
have d
iscovered that during the progression
of evolution
, a
collection
of proteins whose function in yeast
is to pre
serve
cell walls
,
has
found
another use in vertebrates regulation
angiogenesis. This
outstanding
repurposing of
the
proteins during evolution led them
to hypothesize
that, regardless of
the
different functions of the proteins in humans compared
to yeast,
drugs that
moderated
the y
east pathway might also moderate
angiogenesis in humans and in
the
animal models. One compound
seemed to be
exceptionally promising applicant
for this sort of approach: thiabendazole(T
B
Z), which has been in clinical use as a
deworming treatment and
sy
stemic antifungal
treat
ment for 40 years. T
here study
shows that TBZ is
able to act as a vascular disrupting agent
and an
angiogenesis
inhibitor.
TBZ also slowed
tu
m
or growth and reduced
vascular density in human
tumors grafted
into mic
e. TBZ’s historical safety data
low cost make it an
exceptional candidate for conversion
to clinical use as complement to current anti
-
angiogenic strategies fo
r
the treatment of cancer. Their
work demonstrates
how
model organisms from distant
bra
nches of the ev
olutionary tree can be used
to
arrive at a promising new drug.
Materials and Methods
Clustering analysis
Genetic interaction profiles were downloaded from a Standford website. They used
the
p
values stated for fitness defects in the yeast h
omozygous deletion collection
.
A
ll examination
Candidate angiogenesis
inhibitors were prioritized and
consistently
clustered with lovastatin across different choices of similarity measures and
hierarchical
clustering procedures
, s
pecifically centered and
un
-
centered
correlation,
Euclidean distance,
spearman rank correlation, absolute correlation,
and
the
city
-
block distance, using
single linkage,
centroid linkage,
complete linkage
,
or average linkage clustering. Clustering
results were shown
with cluster
3.0.
Xenopus embryo manipulations
Mature
female Xenopus were ovulated by injecting human chorionic
gonadotropin, and eggs were fertilized in vitro and dejellied in 3% cysteine
solution.
They were
then
reared in marc
’s modified ringers’s solution. Microi
njections,
embryos were placed in a solution of 2% ficoll to stage 9, then washed and raised in
a solution alone. This helped them see how the drug effected embryos.
Morpholino Oligonucleoides and cDNA Clones
Aplnr and erg cDNA’s were taken form open bi
osystems. Tra
nslation
-
blocking were
based on sequences from the national center for biotechnology
information database.
MO’s were taken from gene tools
with the resulting
sequence: CGTATTCGTCATCTCTGGCTCCCAT.
Many other methods were used, Cell Culture, In Vitro Angiogenesis Assays,
Cell Migration Assays, Xenograft
Assays, Xenograft Model, Immunohistochemistry,
Imaging and image analysis, Mass spectrometry, and Western Blotting and Elisa. All
of these methods he
lped to support their research.
Results a
n
d discussion
The
saving
of a genetic module that con
t
rols lovastatin sensitivity in yeast
and angiogenesis in ver
t
ebrates
led them to test the likelihood
that small
-
molecule
inhibitors modulat
ing the yeast pathwa
y might
act as ang
iogenesis inhibitors. Initial
evidence suggests that lovastatin itself at least part
ly inhibits angiogenesis and can
even reduce the incidence of melanoma. The
y
developed
a strategy to exploit the
evolutionary repurposing of thi
s module i
n order to direct their
search
. They
desired to distinguish
comp
ou
nds in a manner that did not require th
e
ir me
chanism
of actio or
biochemical target to match that of lovastatin; they employed a genetic
strategy
in yeast in order to choose
comp
o
unds that
genetically
interacted with the
module. By comp
utationally pulling out
available large
-
scale chemical sensitivity
datasets candidate comp
ounds were selected
based upon their measured synthetic
genetic interactions with yeast genes, using c
lustering algor
ithms to recognize
those
comp
o
unds with genetic interaction
profiles most alike
to that of lovastatin.
Four
out of eight prioritized chemicals were already known to modulate angiogenesis,
indicating
sturdy
enrichment for angiogenesis effectors.
The compo
und
T
hiabendazole stood out because it has already been
approved by the FDA for systemic oral use in humans. TBZ is under the trade name
Apl
-
Luster, Mycozol, Teto, and a
rboct. Its safety has been well established
in
animals, TBZ has no carci
n
ogenic effects
in studies at
doses up to 15 times the
normal
human dose. TBZ
doesn’t
appear to a
ffect fertility in rats or mice,
and it
’
s not
a mutagen. TBZ was a great candidate for further s
t
udy.
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