Possible Treatment for Cancer? 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 non-Hodgkin’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 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?related-urls=yes&legid=pnas;103/7/2268 http://radiology.med.sc.edu/Interstitialpulmonaryedema.htm http://www.brookscole.com/chemistry_d/templates/student_resources/0030973694_garrettgrisham/HotTopics/Immunotoxin.html