Fluorescence indicates chlorotoxin binding to medulloblastoma cells in a mouse (right). Credit: Image by Mandana Veiseh, courtesy of AACR Within minutes after being stung by the scorpion known as the deathstalker (Leiurus quinquestriatus), weakness starts to kick in. The feeling quickly spreads, paralyzing its prey (typically insects) for hours -" /> Fluorescence indicates chlorotoxin binding to medulloblastoma cells in a mouse (right). Credit: Image by Mandana Veiseh, courtesy of AACR Within minutes after being stung by the scorpion known as the deathstalker (Leiurus quinquestriatus), weakness starts to kick in. The feeling quickly spreads, paralyzing its prey (typically insects) for hours -" />
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Scorpion tags tumors

Fluorescence indicates chlorotoxin binding to medulloblastoma cells in a mouse (right). Credit: Image by Mandana Veiseh, courtesy of AACR" />Fluorescence indicates chlorotoxin binding to medulloblastoma cells in a mouse (right). Credit: Image by Mandana Veiseh, courtesy of AACR Within minutes after being stung by the scorpion known as the deathstalker (Leiurus quinquestriatus), weakness starts to kick in. The feeling quickly spreads, paralyzing its prey (typically insects) for hours -

By | October 1, 2007

<figcaption>Fluorescence indicates chlorotoxin binding to medulloblastoma cells in a mouse (right). Credit: Image by Mandana Veiseh, courtesy of AACR</figcaption>
Fluorescence indicates chlorotoxin binding to medulloblastoma cells in a mouse (right). Credit: Image by Mandana Veiseh, courtesy of AACR

Within minutes after being stung by the scorpion known as the deathstalker (Leiurus quinquestriatus), weakness starts to kick in. The feeling quickly spreads, paralyzing its prey (typically insects) for hours - just enough time for the scorpion to enjoy dinner. The deathstalker is among the world's most poisonous scorpions, and while humans usually recuperate from its nasty sting, the venom can prove fatal to children, the elderly, and those with compromised immune systems. Which makes its newly proposed clinical benefits all the more surprising.

In 1983, Gary Strichartz, a Harvard anesthesia researcher, began testing the effects of toxins within deathstalker venom. Spider and scorpion venom usually induce paralysis in prey by blocking ion channels involved in muscle contraction, so he hoped that venom proteins would act on sodium channels that the lab was studying. During an experiment designed to focus on one sodium channel, Strichartz's lab noticed a second channel that kept popping up, interfering with the project. They identified the errant channel as a chloride channel, and they found one ingredient of the deathstalker venom that shut it down. They dubbed the peptide, fittingly, "chlorotoxin."

Chlorotoxin proved an interesting find. In 1995, Harald Sontheimer, a neurobiology researcher at the University of Alabama, Birmingham, found that chlorotoxin binds exclusively to glioma, the cancerous cells of brain tumors, but not to normal cells - meaning that chlorotoxin alone was harmless to humans. Seven years later, the Sontheimer lab published an article in the Journal of Biological Chemistry (278:4135-44, 2002) showing that chlorotoxin binds to the matrix metalloproteinase II complex (MMPII). This enzyme degrades the extracellular matrix, doing away with chloride channels in the membrane. Human cells rarely express MMPII, but glioma cells, which are constantly restructuring, express MMPII almost all the time.

Glioma cells "move around a lot, making degradation of the extracellular matrix, and subsequently the MMPII complex, an ever-present necessity," Sontheimer says. He also found that cockroach cells express the MMPII complex, perhaps explaining why insects are so vulnerable to deathstalker venom.

Soon after Sontheimer's discovery, James Olson, an oncology researcher and clinician at the Fred Hutchison Cancer Research Center in Seattle, set his lab on a treasure hunt: Find a technique to tag invisible tumor cells to enable surgeons to remove more wayward cancerous cells. Like many who treat children with brain tumors, Olson was disheartened by the number of patients whose illness persisted after surgery because doctors couldn't spot lingering, invisible cells. The student assigned to the project, Patrik Gabikian, wanted to run snazzy microarray or proteomics experiments, but Olson had a different idea. "I told him to sit down and be patient, and do a literature review," says Olson. He wanted to identify proteins that had been previously researched, rather than starting from scratch with expression studies.

Gabikian found Sontheimer's paper describing chlorotoxin and its affinity for brain tumor cells. The team attached the fluorescent marker CY5.5 to the peptide, and it did exactly what the researchers hoped: Animal tumors glowed within hours after the drug was injected (Cancer Res, 67:6882-8, 2007).

Chlorotoxin spotted as few as 2,000 cancer cells - making it 500 times more powerful than MRI, which typically requires at least one million cells to elucidate a tumor. If usable, doctors will no longer have to wait for postoperative X-rays to find out if they excised the entire tumor; using chlorotoxin, surgeons can spot tumor cells with a naked eye, under infrared light.

Olson is headed toward Phase I trials of the fluorescently labeled chlorotoxin in humans. A Cambridge, Mass.-based startup, TransMolecular, which Sontheimer founded, is also testing a version of chlorotoxin that pinpoints tumors and delivers a low dose of radiation. Olson acknowledges that it might take patients some time to adjust to the idea of being injected with an ingredient from a deadly poison, even one that is harmless to humans. "We aren't sure what patients will say when they hear the molecule comes from scorpion venom."

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Comments

October 12, 2007

As may be obvious, this article raises more possible treatment modalities provided that the blood-brain barrier can be appreciably surmounted.Conjugating the peptide with a toxin such as ricin might be effective in destroying the targeted glioma cells. As I recall, such a procedure has been tried previously on EGF receptors that are amplified in certain tumors, but the therapeutic results were disappointing. In the experiments suggested by the authors, perhaps, the use of radiolabelled material may be more successful.

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Mettler Toledo
BD Biosciences
BD Biosciences