Death cap mushroom poison to arrest pancreatic cancer in mice
The mere thought of an identification error sends a chill down the spine of any mushroom lover: The death cap mushroom (Amanita phalloides), which resembles the common white button mushroom, contains one of the most deadly poisons found in nature, α-amanitin. This substance kills any cell without exception, whether it be healthy or cancerous. At the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the National Center for Tumor Diseases Heidelberg, immunologist Dr. Gerhard Moldenhauer, jointly with biochemist Professor Dr. Heinz Faulstich, Max Planck Institute for Medical Research, has now developed a method for destroying cancer cells using the dreaded fungal toxin without harming the body.
The trick to accomplish this is to deliver the poison directly to the right address in the body using something that virtually serves as a cab. In this case, the cab is an antibody whose highly specific arms attach to a cancer-typical cellular surface protein called EpCAM. The fungal toxin is linked to the antibody in a stable chemical conjugation.
In the culture dish, the poison-loaded antibody arrested the growth of pancreatic, colorectal, breast and bile duct cancer cell lines. In mice bearing transplanted human pancreatic cancer, a single antibody injection was sufficient to inhibit tumor growth. Two injections of higher doses of the antibody even caused complete tumor regression in 90 percent of the animals. Even the higher doses did not cause any poison-related damage to the liver or other organs of the animals.
EpCAM, the protein chosen by the Heidelberg immunologists as the tumor cell recognition structure, is a characteristic membrane protein of epithelial cells. This type of cells lines all inner and outer surfaces of the body. Most malignant tumors originate from such epithelial tissues. Many of these, such as pancreatic cancer, breast and ovarian cancers, bile duct carcinomas and tumors of the head and neck, produce too much EpCAM and this is frequently associated with an extremely poor prognosis of the disease. EpCAM is therefore considered a suitable target structure for attacking tumor cells.
"Treatments with unconjugated antibodies against EpCAM have already been tested in clinical trials such as for breast cancer. They were intended to attack the cancer solely with the weapons of the immune system, but they turned out to be clinically ineffective," said Gerhard Moldenhauer. "However, our amanitin-conjugated antibody has a much greater potential for killing cancer cells."
Details are of vital importance
Each antibody is linked to between four and eight toxin molecules. Amanitin is regarded as very suitable for this purpose. It is small enough not to be recognized as foreign by immune cells, while it is also robust enough to lend itself to chemical conjugation. "When developing toxin-conjugated antibodies you have to take an awful lot of things into account," Moldenhauer explains. "The cancer cell has to regularly take the target molecule including the attached antibody into its interior, for this is the only place where the poison can act. In the cell's interior, the poison needs to detach from the antibody or else it will not be effective. At the same time it is absolutely vital that it does not get lost while it is being carried through the body, because this could cause severe adverse side effects."
The dosage of the amanitin antibody needs to be determined with the utmost care. One problem is that liver cells are extremely sensitive to the fungal toxin; another is that other healthy cells carry the EpCAM molecule as well and are therefore endangered. However, the results obtained in mice give reason to be optimistic, according to Gerhard Moldenhauer: "Even at high doses we have not detected any organ damage in the animals. We therefore expect that there is a sufficient therapeutic window for a dosage that kills cancer cells while leaving healthy tissue unaffected."
Moldenhauer, who has many years of experience in developing therapeutic antibodies, already has plans for amanitin-conjugated guided missiles against other cancers. In particular, certain types of leukemia and lymphoma cells also carry highly specific surface molecules which lend themselves as target structures for poison-loaded antibodies.
More information: Gerhard Moldenhauer, Alexei V. Salnikov, Sandra Luttgau, Ingrid Herr, Jan Anderl and Heinz Faulstich: Therapeutic Potential of Amanitin-Conjugated Anti-Epithelial Cell Adhesion Molecule Monoclonal Antibody Against Pancreatic Carcinoma. JNCI Journal of the National Cancer Institute 2012; DOI: 10.1093/jnci/djs140
Provided by Helmholtz Association of German Research Centres
- Polymer film loaded with antibodies that can capture tumor cells shows promise as a diagnostic tool Feb 24, 2012 | not rated yet | 0
- Enhancing the effectiveness of a breast cancer treatment Feb 13, 2012 | not rated yet | 0
- Bright future ahead for antibody cancer therapy Mar 15, 2012 | not rated yet | 0
- Pancreatic cancer fights off immune attack Aug 30, 2007 | not rated yet | 0
- Researchers boost immune 'killer cells,' increase antibody effectiveness against cancer Apr 18, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer May 24, 2013 | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer May 24, 2013 | 5 / 5 (1) | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer May 24, 2013 | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer May 24, 2013 | 5 / 5 (2) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer May 24, 2013 | 5 / 5 (4) | 0
Coenzyme Q10 decreases all cause mortality by half, according to the results of a multicentre randomised double blind trial presented today at Heart Failure 2013 congress. It is the first drug to improve heart failure mortality ...
6 hours ago | 5 / 5 (2) | 4
Heart failure accelerates the aging process and brings on early andropausal syndrome (AS), according to research presented today at the Heart Failure Congress 2013. AS, also referred to as male 'menopause', was four times ...
6 hours ago | not rated yet | 1
Mortality and length of stay are highest in heart failure patients admitted in January, on Friday, and overnight, according to research presented today at the Heart Failure Congress 2013. The analysis of nearly 1 million ...
6 hours ago | not rated yet | 0
(AP)—Department of Justice lawyers have again asked a federal appeals court in New York to delay lifting age restrictions and prescription requirements on an emergency contraceptive popularly known as the morning-after ...
6 hours ago | not rated yet | 0
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
22 hours ago | 3 / 5 (2) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
22 hours ago | not rated yet | 0