ASHLEY SANCHEZ ANDREA POHL VANESSA MICHEL CHLOROTOXIN
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Toxins What is a toxin? A toxin is a poisonous substance that
is a specific product of the metabolic activities of a living
organism. It is usually very unstable, notably toxic when
introduced into the tissues, and typically capable of inducing
antibody formation. What is a neurotoxin? A neurotoxin is a
substance that damages, destroys, or impairs the functioning of
nerve tissue.
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What is chlorotoxin? "Chlorotoxin (CTX), a 4-kD peptide
purified from Leiurus quinquestriatus scorpion, is a highly
specific marker for glioma cells in biopsy tissues that can target
tumors in animal models. Put more simply: "Chlorotoxin is a
36-amino acid peptide found in the venom of the deathstalker
scorpion (Leiurus quinquestriatus) which blocks small- conductance
chloride channels."
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Why we chose chlorotoxin? We found the venom, Chlorotoxin, to
be very interesting because of its possible impact on cancer
treatment, especially brain cancer, which has faced many obstacles
in finding safe, effective treatment. The source of the toxin is
from the venom of a scorpion, which further emphasizes that toxins
can be harmful but also potentially beneficial depending on the
dose.
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Where does chlorotoxin come from? Chlorotoxin can be purified
from crude leiurus, which belongs to scorpion toxin super
family.
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Leiurus quinquestriatus Habitat Deathstalkers are found in arid
and hyper-arid regions of North Africa and the Middle East. They
generally reside under rocks or in abandoned burrows of other
animals. They also create their own burrows about 20 cm below
rocks. Geographic range "Deathstalkers, Leiurus quinquestriatus,
are native to the Oriental, Palearctic, and Palearctic regions.
Behaviors Deathstalkers are nocturnal, which helps manage
temperature and water balance, important functions for survival in
dry habitats. Many species of scorpions dig burrows in the soil.
They have flat bodies, allowing them to hide in small cracks, under
rocks and under bark
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Mechanism Deathstalker scorpion venom contains chlorotoxin
which can have serious effects on the individual who is stung. The
shape of chlorotoxin is very important. It is the perfect shape to
fit in Chloride ion channels, and irreversibly block them. By doing
this, it prevents the muscle cell from receiving an influx of
chloride ions which it usually recieves for normal muscle
functioning. This results in muscle contraction, and possibly
paralysis.
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What to do if stung It is vital to receive medical attention as
soon as possible after a sting. Although painful, few people die
but those with allergies or heart issues are at greater risk of
death if stung. It is important to apply ice in the area of the
sting. Treatment includes the administration of anti- venom, pain
medication and some antihistamines. Symptoms will vary among
patients. Some experience a wide array of symptoms while others
experience mild symptoms.
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Anti-venom Treatment Although the Deathstalker Scorpion is
regarded as one of the most toxic scorpions, stings are not usually
fatal. There is an anti-venom which is used for the treatment of
Deathstalker stings. It has no effect on Chlorotoxin proteins that
are already blocking Chloride channels, but rather works by
changing the shape of Chlorotoxin so it cannot bind and block
Chloride channels. Preventing the problem from getting worse.
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Ancient Uses of Scorpion Venom In imperial China, scorpion
venom was used to treat ailments such as mumps and tetanus In
India, whole scorpions were dipped in mustard oil and rubbed on
arthritic joints to treat pain
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Chlorotoxin and Gliomas In 1996, Ullrich and Sontheimer found
that Chlorotoxin was effective in blocking chloride channels in
glial cells by as much as 80%. They also found that cell
proliferation decreased as chloride channels were blocked,
suggesting a link between the chloride channels and growth control.
Soroceanu et al (1998) found the toxin probably binds to
glioma-specific chloride ion channels or another receptor that
affects the channels activity.
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Chlorotoxin and Other Cancer Cells In 2002, Lyons et al found
that Chlorotoxin can bind to a number of tumor cells, even though
they have different membrane composition. They stained tissues from
48 various peripheral tumors of neuroectodermal origin, 63 from
gliomas and 151 comparison tissue samples with a chlorotoxin
derivative. Comparison tissue samples were healthy tissues from the
same organ. Over 95% of the glioma cells showed specific binding of
the chlorotoxin derivative. The chlorotoxin derivative bound well
to other brain tumor cells, as well as melanoma, carcinoma and
pheochromacytoma tissues. Healthy tissues were mostly untouched by
the toxin.
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Medical Possibilities for Chlorotoxin Dr. Steven Rosenfeld is
conducting a series of trials at the NewYork-Presbyterian using
radioactive and non-radioactive chlorotoxin to inhibit
angiogenesis, or the tumors ability to grow blood vessels. The
first clinical, which has been completed, saw radioactive
chlorotoxin delivered locally to the brain tumor site via a thin
catheter. In the second trial, which is currently underway,
patients are receiving a non-radioactive chlorotoxin delivered
intravenously. The third trial will see patients receiving
radioactive chlorotoxin intravenously.
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Medical Possibilities for Chlorotoxin Tumor Paint Dr. Jim Olson
is working on developing a chlorotoxin biconjugate that will stain
cancer cells so surgeons can more easily remove the tumor during
surgery. Tumor Paint attaches to cancerous cells and illuminates
them so surgeons can distinguish them from healthy cells.
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CTX Nanoparticles Chlorotoxin (CTX) is an up and coming
important toxin in the development of glioma- specific
nanoparticles. Chloride channels are CTX receptors, and matrix
metalloproteinase-2 (MMP-2) has been identified as a second CTX
receptor. MMPs are a family of enzymes that are responsible for
specifically cleaving components of the extracellular matrix. MMP-2
is upregulated in gliomas and other related cancers.
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Medical Possibilities for Chlorotoxin Gene Therapy In a study
by Kievit et al, researchers developed nanoparticles that had DNA
encoding green fluorescent expression and attached them to
chlorotoxin. They studied gene delivery to glioma cells in mice.
There was enhanced uptake of these particles in cancer cells, as
evidenced by higher gene expression. The DNA-attached chlorotoxin
saw much higher localized expression of the green fluorescent
protein in tumor cells
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Medical Possibilities for Chlorotoxin The research on this
toxin has shown the great potential it has to further cancer
treatment. Its ability to affect cancer cells without harming
healthy cells makes it a safe alternative to current treatments
such as chemotherapy. It can potentially help inhibit growth of
tumors, deliver genes that can act on cancer cells, and light up
tumors, helping surgeons remove whole tumors while leaving healthy
tissue unharmed.
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The Good Chlorotoxin was originally isolated from venom of
deathstalkers and is now being used in cancer research and
treatment. More research is being done in regards to the possible
use of other components of deathstalkers venom in the treatment of
diabetes because as channels on which the neurotoxins act have been
linked to the regulation of insulin. However, such research is
still in its early stages. Scorpions are also good bio-indicators,
as they are K-selected equilibrium species that comprise a major
group of predatory arthropods in arid ecosystems. Their
disappearance often indicates habitat degradation and there are
programs to conserve terrestrial invertebrates that often target
scorpions.
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The Bad Deathstalker scorpions use venom as a defense
mechanism. As a result, this can have very painful (and sometimes
deadly) consequences for the individual stung.
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Why you should care Chlorotoxin has exhibited itself to be a
useful peptide in the research and treatment of different cancers
and medical issues. This toxin has a major impact on the medical
world, as well as in the lives of those with cancer. The main
take-home message that is further exhibited by chlorotoxin is that
toxins can be harmful AND helpful.
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Works Cited Fu, y., An, N., Li, K., Zheng, Y., Liang, A.
(2011). Chlorotoxin-conjugated nanoparticles as potential
glioma-targeted drugs. Journal of Neuro- Oncology. 107:457-462.
Kievit, F. M., Veiseh, O., Fang, C., Bhattarai, N., Lee, D.,
Ellenbogen, R. -G., and Zhang, M. (2010). Chlorotoxin labeled
magnetic nanovectors for targeted gene delivery to glioma. ACS
Nano, 4.8: 4587-94. Lyons, S. A., O'Neal, J. and Sontheimer, H.
(2002), Chlorotoxin, a scorpion- derived peptide, specifically
binds to gliomas and tumors of neuroectodermal origin. Glia, 39:
162173. Soroceanu, L., Gillespie, Y., Khazaeli, M. B., and
Sontheimer, H. (1998). Use of chlorotoxin for targeting of primary
brain tumors. Cancer Research, 1.58: 4871-9. Ullrich, N. and
Sontheimer, H. (1996). Biophysical and pharmacological
characterization in human astrocytoma cells. American Journal of
Physiology, 270.5: 1511-21.