Thiabendazole the antifungal drug is a vascular disrupting agent.

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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.