Transcript Ricin - Faculty Sites at the University of Central Arkansas

Ricin
Possible Treatment for Cancer?
What is Ricin?
• A poison found naturally in
beans of caster bean plant,
Ricinus communis
– Family Euphorbiaceae
– Native to tropical Africa
• Can be in form of powder,
mist, or pellet, or dissolved
in water or weak acid
• A stable substance under
normal conditions
Where is Plant Found and How is it Used?
• Castor beans are
processed
throughout world
to make castor oil
– Castor beans grow
wild everywhere
Castor Oil was once used as an oral laxative, but is now used mainly as an industrial
lubricant and for preparing leather products
How is Ricin Purified?
• Part of waste “mash”
produced when castor
oil is made
– Does not need to be
purified
• Mashing up beans
produces crude toxin
powder that is very stable
– An estimated 50,000
tons available in world
today
How Can You Be Exposed to Ricin?
• Not contagious; Can not be
spread by person to person
contact
• Can be used to expose
people through air, food, or
water
• Possibly as warfare agent
Chemical Nature of Ricin
• Tertiary structure is globular, heterodimer
– Ribotoxic A chain (RTA) and B chain (RTB)
• Ricin A is of extremely low toxicity as long as
B chain is not present
– Many plants have A chain but not B chain (i.e. Barley)
• Entering cell depends on hydrogen bonding
interactions between RTB and carbohydrates
on eukaryotic cell surface
How Does Ricin Work?
• Inhibits protein synthesis
by inactivating ribosomes
• Effects of poisoning
depend on dose and
whether ricin was
inhaled, ingested, or
injected
• Perhaps one milligram of
ricin can kill an adult
Signs and Symptoms of Ricin Exposure
• Death could take place 36 to 72 hours of
exposure
• Initial symptoms by inhalation occur within 8
hours of exposure
– Respiratory distress, fever, cough, nausea, and
tightness in chest
– Heavy sweating and pulmonary edema follow
– Low blood pressure and respiratory failure
Signs and Symptoms Cont.
• Initial symptoms by ingestion occur in less
than 6 hours
– Vomiting and diarrhea
– Severe dehydration and low blood pressure
– May include hallucinations, seizures, and blood in
urine
– Several days after, liver, spleen, and kidneys may
stop working, resulting in death
• Skin and eye contact cause redness and pain
How Do Authorities Confirm Cases of
Suspected Ricin Poisoning?
• No widely available, reliable medical test
– People observed for signs of poisoning
• Environmental testing by public health and
law enforcement
– Try to detect ricin in powders or materials
released into environment
Disease Control and Prevention
• Biothreat
– Easily produced
– Readily available
– Highly stable
• More than 750 cases of
documented ricin
intoxication
How is Ricin Poisoning Treated?
• No vaccine or prophylactic antitoxin available
– Immunization appears promising in animal models
– Most important factor is getting ricin off or out of
body as quickly as possible
• Symptomatic poisoning treated by supportive
medical care
– Types of supportive care depends on type of
exposure
What Should You Do In Case of Exposure?
• Leave area where ricin
was released
• Remove clothing,
rapidly wash entire
body with soap and
water, and get medical
care as quickly as
possible
Ricin Benefits
• Use as immunotoxin
• Medical research
– Abundant and easy to
manipulate
– Vaccine research
• Protection for troops
and public against
bioterrorist attack
Other Uses
• Suicidal and homicidal
purposes
– United Kingdom
• Death of Georgi Ivanov
Markov in 1978
– Ricin via a tiny pellet
• London in 2003
– Suspicion of
manufacturing toxin
for terrorist purposes
– United States
• Ricin detected in mail at
white house in 2003
Experimental Uses in Medicine
Dr David Flavell, University
of Southampton
• Potential for immunotoxins
– Binds to cancer cell, is
internalized and kills cell
– Antibody targets only
cancer cells and normal
cells spared
Experimental Uses Cont.
• Conjugate RTA subunit and
antibodies or growth
factors bind cancer cells
– Worked well for in vitro
• Successful in
destroying T
lymphocytes in bone
marrow
Experimental Uses Cont.
• Some given treatment
developed vascular
leak syndrome
– Walls of blood
vessels allow plasma to
seep into the tissues
• Fluid retention, increase
in body weight,
interstitial edema
Experimental Uses Cont.
Team from the University of Texas Southwestern
Medical Center
• Engineered toxin lacking proteins that caused
vascular leak syndrome
– Modified toxin was efficient at killing tumor cells
– Concluded dose of toxin in future cancer drug
should be increased, making it more effective
against disease
• Research was published in the journal Nature
Biotechnology
Experimental Uses Cont.
• Immunotoxins are
completing Phase I and II
trials in patients with
Hodgkin’s and nonHodgkin’s lymphoma
• Preclinical studies for
clinical trial in pediatric
lymphocytic leukemia
• Immunotoxins under
development to prevent
graft-versus-host disease
Pilot Clinical Trial of
Recombinant Ricin Vaccine
Ellen S. Vitetta UT Southwestern
• Recombinant A chain (RTA) with two amino
acid substitutions disrupts ribotoxic site
– Recombinant RTA (named RiVax) produced
and purified in E. coli
– RiVax injected i.m. into mice
• Proved effective and safe
Pilot Clinical Trial of Vaccine Cont.
• Pilot clinical trial under investigational new drug
application by Food and Drug Administration
– Study:
• Three groups of five volunteers injected three times
monthly with 10, 33, or 100 μg of RiVax
• Vaccine was safe and elicited Abs in one of five
individuals in the low-dose group, four of five in the
intermediate-dose group, and five of five in high-dose
group
• Results justify further development of vaccine
References
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http://www.bt.cdc.gov/agent/ricin/qa.asp
http://news.bbc.co.uk/2/hi/health/2837763.stm
http://www.actionbioscience.org/newfrontiers/vitetta.html
http://www.jmedcbr.org/issue_0701/Kumar/Kumar_01_09.html
http://www.ehso.com/ricin.php
http://www.pnas.org/content/103/7/2268.abstract?relatedurls=yes&legid=pnas;103/7/2268
• http://radiology.med.sc.edu/Interstitialpulmonaryedema.htm
• http://www.brookscole.com/chemistry_d/templates/student_resou
rces/0030973694_garrettgrisham/HotTopics/Immunotoxin.html