Synthetisch gemaakt schorpioenengif - TM-106 geeft opmerkelijk goede resultaten bij mensen met een hersentumor

20 juli 2011: schorpioenengif blijft een interessant middel in een behandeling tegen kanker. In 2009 werd een studie gepubliceerd waarbij schorpioenengif werd getest bij mensen met een hersentumor aangevuld met nanodeeltjes en met goede resultaten. Onderaan heb ik het abstract van die studie toegevoegd aan eerder geplaatste studies, zie hieronder.

6 augustus 2007: Bron: J Clin Oncol. 2006 Aug 1;24(22):3644-50,

Met dank aan Wim voor deze tip.

Enkele studies wijzen uit dat de werkzame stof uit schorpioenengif, als eiwit synthetisch geproduceerd onder de naam TM-106, goede resultaten geeft bij kankerpatienten met een hersentumor van het type glioma nadat bij deze patienten na operatie een recidief was ontstaan en in principe verder onbehandelbaar waren geworden. Eèn studie met 18 patienten wijst uit dat 3 van de 18 minimaal drie jaar overleefden en nog eens 6 van de 18 leefden beduidend langer dan statistisch mocht worden verwacht. Statistisch gezien, aldus de onderzoekers, overleeft niemand een recidief van een hersentumor van het type glioma. Twee andere studies wijzen op dezelfde resultaten, zie hieronder de abstracten. Nu is al langer bekend dat schorpioenengif , meestal gehaald uit Cuba, dat dit werkzaam is tegen kanker. Het is niet het wondermiddel dat alle kanker doodt maar zoals ook de studies , gepubliceerd hieronder uitwijzen, een bepaald stofje uit het schorpioenengif, bindt zich aan bepaalde kankercellen en laat gewone cellen met rust. Zo zijn er studies gedaan waarbij een radioactieve stof ( intracavitary-administered iodine-131-TM-601 ) werd verbonden aan dit synthetisch gemaakte gif dat de kankercellen opzoekt en daar doodt. Maar uit de studies blijkt nu ook dat het synthetisch gemaakte gif op zichzelf ook kankercellen doodt. Zie hieronder drie studies over hetzelfde schorpioenengif synthetisch geproduceerd.

Scorpion Venom Tested Against Brain Cancer
07.28.06, 12:00 AM ET

FRIDAY, July 28 (HealthDay News) -- A synthetic version of a protein found in scorpion venom has passed its first test in a treatment for one of the deadliest forms of cancer and is headed toward trials against other tumors.
The protein, designated TM-601, not only carried radioactive iodine directly to the brain tumor called glioma, but also appeared to have anticancer activity of its own, said Dr. Adam N. Mamelak, a neurosurgeon at the Cedars-Sinai Medical Center's neurosurgical institute in Los Angeles. He was lead author of a report on the therapy in the August issue of the Journal of Clinical Oncology. TM-601 has an unusual ability to pass through the blood-brain barrier that keeps most chemicals from reaching brain tissue. It also binds to glioma cells, which are vulnerable to the radioactive iodine carried by the protein, Mamelak said.
The treatment was tried in 18 patients whose glioma recurred after surgery, which usually means death within months.
"Two of the 18 patients had long survival, about three years post-treatment," Mamelak said. "Six of 18 survived significantly longer that the typical patient population." An estimated 17,000 Americans are diagnosed with gliomas each year. These tumors are extremely aggressive and deadly; only 8 percent of patients survive two years and 3 percent survive five years after diagnosis. And when surgery is performed to remove a glioma, some malignant cells invariably remain behind and proliferate, the researchers said. TM-601 was developed in the laboratory of Harold Sontheimer, a neurobiologist who heads the Civitan Research Center of the University of Alabama at Birmingham. It acts by blocking chloride channels in cells, Sontheimer explained, the same action that helps paralyze cockroaches, the prey of the Giant Yellow Israeli scorpion. In humans, that action prevents tumor cells from invading surrounding tissue, he said.
TM-601 has been licensed to a Birmingham, Ala., company, TransMolecular Inc., which helped finance the study. It was a Phase 1 trial, the first step in the long process of gaining U.S. Food and Drug Administration approval for medical use.
One major purpose of a Phase 1 trial is to test safety, and "we were very pleased that there was a very good safety profile," said Michael Egan, president and chief executive officer of TransMolecular. "There was essentially no toxicity," added Mamelak. "Whatever didn't bind to the tumor didn't go anywhere. It was washed out of the body."
A Phase 2 trial that will enroll 54 glioma patients at 20 medical centers around the country has begun recruiting participants, Egan said. One purpose of the trial will be to determine the best dosage schedule, he said. Results are expected some time next year.
Plans are also being made for trials of TM-601 against other forms of cancer, Egan said. The targets would be "multiple solid tumor types, any solid tumor," such as breast cancer or colon cancer, he said. There are indications that TM-601 is more than just a radiation carrier, Mamelak said. "The idea is that it may be synergistic and potentiate the effects of other therapies," he said. The nasty side of venom was the subject of another report, this one by researchers at Stanford University School of Medicine. It has been thought that the body's immune system worsens the nausea, numbness, convulsions and other effects of venom. But mouse studies of four venoms -- three from snakes and one from a bee -- showed the immune system did fight the ill effects of those venoms, reducing the symptoms, said the report in the July 28 issue of Science.

More information To learn more about brain tumors, visit the U.S. National Library of Medicine.

1: J Clin Oncol. 2006 Aug 1;24(22):3644-50.
Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma.Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash JB, Shen S, Khazaeli MB, Colcher D, Liu A, Osman M, Guthrie B, Schade-Bijur S, Hablitz DM, Alvarez VL, Gonda MA. Maxine Dunitz Neurosurgical Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Adam.Mamelak@cshs.org

PURPOSE: TM-601 binds to malignant brain tumor cells with high affinity and does not seem to bind to normal brain tissue. Preclinical studies suggest that iodine-131 (131I) -TM-601 may be an effective targeted therapy for the treatment of glioma. We evaluated the safety, biodistribution, and dosimetry of intracavitary-administered 131I-TM-601 in patients with recurrent glioma.

PATIENTS AND METHODS: Eighteen adult patients (17 with glioblastoma multiforme and one with anaplastic astrocytoma) with histologically documented recurrent glioma and a Karnofsky performance status of > or = 60% who were eligible for cytoreductive craniotomy were enrolled. An intracavitary catheter with subcutaneous reservoir was placed in the tumor cavity during surgery. Two weeks after surgery, patients received a single dose of 131I-TM-601 from one of three dosing panels (0.25, 0.50, or 1.0 mg of TM-601), each labeled with 10 mCi of 131I.

RESULTS: Intracavitary administration was well tolerated, with no dose-limiting toxicities observed. 131I-TM-601 bound to the tumor periphery and demonstrated long-term retention at the tumor with minimal uptake in any other organ system. Nonbound peptide was eliminated from the body within 24 to 48 hours. Only minor adverse events were reported during the 22 days after administration. At day 180, four patients had radiographic stable disease, and one had a partial response. Two of these patients further improved and were without evidence of disease for more than 30 months.

CONCLUSION: A single dose of 10 mCi 131I-TM-601 was well tolerated for 0.25 to 1.0 mg TM-601 and may have an antitumoral effect. Dosimetry and biodistribution from this first trial suggest that phase II studies of 131I-TM-601 are indicated.

PMID: 16877732 [PubMed - indexed for MEDLINE]

1: Expert Opin Drug Deliv. 2007 Mar;4(2):175-86.
Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601).Mamelak AN, Jacoby DB.
Cedars-Sinai Medical Center, Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Los Angeles, CA8631 W. Third Street, Suite 800e, Los Angeles, CA 90048, USA. mamelaka@cshs.org

Targeted therapies for cancer is a rapidly advancing field, but the identification of tumor-specific ligands has proven difficult. Chlorotoxin (CTX) is a small, 36 amino acid neurotoxin isolated from the venom of the Giant Yellow Israeli scorpion Leiurus Quinquestriatus. Interestingly, the peptide has been found to preferentially bind to a variety of human malignancies, but shows little or no binding to normal human tissues. A synthetic version of this peptide (TM-601) has been manufactured and covalently linked to iodine 131 (131I-TM-601) as a means of targeting radiation to tumor cells. Preclinical studies and Phase I clinical trials have been completed in patients with recurrent glioma, a type of malignant brain tumor. These studies demonstrated that intracavitary dosing of 131I-TM-601 appears safe, minimally toxic, and binds malignant glioma with high affinity and for long durations. A Phase II trial of this agent using higher doses of radioactivity and repeated local administrations is underway. In addition, enrolment has begun in a Phase I trial evaluating whether systemically delivered 131I-TM-601 can be used to image metastatic solid tumors and primary gliomas. Due to its small size, selective tumor binding properties, minimal toxicity and relative ease of manipulation, CTX represents a potentially important targeting agent for many cancers.

PMID: 17335414 [PubMed - indexed for MEDLINE]

1: Neurosci Lett. 2007 Jan 22;412(1):62-7. Epub 2006 Dec 12.
Therapeutic potential of chlorotoxin-like neurotoxin from the Chinese scorpion for human gliomas.Fu YJ, Yin LT, Liang AH, Zhang CF, Wang W, Chai BF, Yang JY, Fan XJ. Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, PR China.

Chlorotoxin, one of the key toxins in scorpion Leiurus quinquestriatus venom, has been shown to bind specifically to glioma cell surface as a specific chloride channel blocker. In this study, a purified, recombinant chlorotoxin-like peptide from the scorpion Buthus martensii Karsch (named rBmK CTa) was characterized by in vivo and in vitro studies. The results from cell proliferation assay with human glioma (SHG-44) cells showed that rBmK CTa inhibits the growth of glioma cells in a dose-dependent manner, with an IC(50) value of approximately 0.28microM. Under the same conditions, the IC(50) value for normal astrocytes increased to 8microM. This clearly indicated that rBmK CTa had specific toxicity against glioma cells but not astrocytes. Results from whole-cell patch-clamp recording showed that chloride current in SHG-44 was inhibited by rBmK CTa in a voltage-dependent manner and percent inhibitions for the blocking action of rBmK CTa (0.07 and 0.14microM) on I(Cl) was 17.64+/-3.06% and 55.86+/-2.83%, respectively. Histological analysis of rBmK CTa treated mice showed that brain, leg muscle and cardiac muscle were the target organs of this toxin. These results suggest that rBmK CTa may have potential therapeutic application in clinical treatment of human glioma. It represents an approach for developing a novel therapeutic agent.

PMID: 17166663 [PubMed - indexed for MEDLINE]

Scorpion venom with nanoparticles slows spread of brain cancer

Bron: Universiteit van Washington

University of Washington

In a , chlorotoxin molecules, colored blue and green, attach themselves to a central nanoparticle. In b , each nanoprobe offers many chlorotoxin molecules that can simultaneously latch on to many MMP-2s, depicted here in yellow, which are thought to help tumor cells travel through the body. In c , over time nanoprobes draw more and more of the MMP-2 surface proteins into the cell, slowing the tumor's spread.

April 16, 2009 | Health and Medicine | Science | Technology
Scorpion venom with nanoparticles slows spread of brain cancer

Hannah Hickey

hickeyh@u.washington.edu

University of Washington

Tumor cells treated with nanoparticles plus chlorotoxin were the only ones unable to elongate and slip through the body, as shown in the third column. The other columns show cancer cells that are: untreated; treated with chlorotoxin alone; and treated with nanoparticles alone. (The upper and lower rows use different types of imaging.)

By combining nanoparticles with a scorpion venom compound already being investigated for treating brain cancer, University of Washington researchers found they could cut the spread of cancerous cells by 98 percent, compared to 45 percent for the scorpion venom alone.

"People talk about the treatment being more effective with nanoparticles but they don't know how much, maybe 5 percent or 10 percent," said Miqin Zhang, professor of materials science and engineering. "This was quite a surprise to us." She is lead author of a study recently published in the journal Small.

For more than a decade scientists have looked at using chlorotoxin, a small peptide isolated from scorpion venom, to target and treat cancer cells.

Chlorotoxin binds to a surface protein overexpressed by many types of tumors, including brain cancer. Previous research by Zhang's group combined chlorotoxin with nanometer-scale particles of iron oxide, which fluoresce at that size, for both magnetic resonance and optical imaging.

Chlorotoxin also disrupts the spread of invasive tumors -- specifically, it slows cell invasion, the ability of the cancerous cell to penetrate the protective matrix surrounding the cell and travel to a different area of the body to start a new cancer. The MMP-2 on the cell's surface, which is the binding site for chlorotoxin, is hyperactive in highly invasive tumors such as brain cancer. Researchers believe MMP-2 helps the cancerous cell break through the protective matrix to invade new regions of the body. But when chlorotoxin binds to MMP-2, both get drawn into the cancerous cell.

Other researchers are currently conducting human trials using chlorotoxin to slow cancer's spread.

Zhang's group investigated chlorotoxin action when it is attached to nanoparticles and found the resultant complex doubles the therapy's effect compared to chlorotoxin alone. Adding nanoparticles often improves a therapy, partly because the combination lasts longer in the body and so has a better chance of reaching the tumor. Combining also boosts the effect because therapeutic molecules clump around each nanoparticle. In the newly published study an average of 10 chlorotoxin molecules were attached to each nanoparticle. Each clump thus offers many therapeutic molecules that can simultaneously latch on to many MMP-2 proteins.

Experiments were performed using mouse brain-cancer cells that were grown in the lab. The imaging results confirm that adding nanoparticles means more of the MMP-2 ends up safely tucked away inside the cell, thus preventing MMP-2 from helping the cancer spread.

Further images showed that the cells containing nanoparticles plus chlorotoxin were unable to elongate, whereas cells containing only nanoparticles or only chlorotoxin could stretch out. This suggests that the nanoparticle-plus-chlorotoxin disabled the machinery on the cell's surface that allows cells to change shape, yet another step required for a tumor cell to slip through the body.

"We hypothesized the mechanism and we have all the data to prove our hypothesis," Zhang said. Further experiments will involve testing on mice.

So far most cancer research has combined nanoparticles either with chemotherapy that kills cancer cells, or therapy seeking to disrupt the genetic activity of a cancerous cell. This is the first time that nanoparticles have been combined with a therapy that physically stops cancer's spread.

Slowing the spread of cancer would be especially useful for treating highly invasive tumors such as brain cancer. MMP-2 also shows signs of being overactive in cancers of the breast, colon, skin, lung, prostate and ovaries, and researchers believe that the technique could slow the spread of these other tumors.

Co-authors are Omid Veiseh, Jonathan Gunn, Forrest Kievit, Conroy Sun and Chen Fang of the UW and Jerry Lee of the National Cancer Institute and Johns Hopkins University. The research was funded by the National Institutes of Health and fellowships from the National Cancer Institute and Ford Motor Company.

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For more information, contact Zhang at 206-616-9356 or mzhang@u.washington.edu .

hersentumoren, schorpioenengif