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Scorpion unlikely source of hope

Deadly venom extends life of some brain cancer patients

By Melissa Healy

Originally published September 1, 2006

In the deserts of the Middle East, the giant yellow Israeli scorpion is a ruthless hunter whose bite can bring on fever, convulsions, coma and, sometimes, heart failure in humans unlucky enough to run afoul of it.

But the same venom that has earned this 4-inch-long arthropod the name "deathstalker" may be the key to longer life for humans under attack from an even more insidious predator.

In a study published in last month's issue of the Journal of Clinical Oncology, researchers made a version of the venom and used it in a new treatment for a deadly brain cancer called glioma. Ultimately it could be used against a wide range of aggressive cancers.

If the venom-based treatment's promising beginnings are borne out in research, it would be among a new generation of "smart weapons" that carry chemotherapy or radiotherapy directly to its target and blast malignant tumors at close range -- with a minimum of collateral damage.

It also would mark the latest advance in a booming new field of medical research that uses naturally occurring toxins to treat human maladies.

"They're finding that venoms are cocktails of extremely powerful compounds -- and when you look into them, you find a cornucopia of potential leads," said David J. Newman, acting chief of the National Cancer Institute's natural products branch.

Researchers in the study, Newman said, "have found one of these and are applying it in a very clever way. And there are many more of them."

In the case of gliomas, effective treatment is overdue. Of the 17,000 Americans diagnosed each year with glioma, fewer than one in 10 lives longer than two years. Neither drugs nor radiation therapy has shown any prospect of meaningfully extending those patients' lives.

The latest study marks the first time that the deathstalker scorpion's venom, a chlorotoxin, has been tested on humans. It's being developed as a drug therapy by Cambridge, Mass.-based Trans molecular Industries Inc.

The unique properties of the giant yellow scorpion's venom -- particularly that one of its key proteins binds only to the receptor sites of cancerous cells -- was first discovered in a microbiology lab at the University of Alabama. The venom's protein is small enough to cross the blood-brain barrier, enabling it to reach cancerous brain tissue.

In the Journal of Clinical Oncology, researchers led by Cedars-Sinai Medical Center neurosurgeon Adam Mamelak describe a trial in which a synthetic version of the deathstalker's venom, dubbed TM-601, carried a very low dose of radioactive iodine to the spider-shaped brain tumors of 18 patients.

The dose of radioactivity was so low that researchers believed it would have, at best, a minimal effect as radiation therapy. The iodine's main purpose was to help researchers track the absorption of the synthetic venom by cells and organs throughout the body.

Three months and six months after the dose was administered, the synthetic venom was found to have deposited itself -- and its radioactive payload -- with precision in the immediate neighborhood of the malignant site. Researchers noted that while the venom's presence in the immediate vicinity of tumors was strong and long-lasting, traces not taken up by the tumor were apparently eliminated quickly from the body and did not accumulate in patients' organs.

Because chemotherapies now in use go to work throughout the body -- not just on malignancies -- they come with debilitating and unintended side effects, including anemia, hair and weight loss, nausea and exhaustion. A medicine that goes to work on cancerous tumors exclusively -- or one that delivers chemotherapy with greater precision -- could reduce those side effects while concentrating its cancer-fighting power on the sites of malignancy.

Four cancer patients participating in the study appeared to suffer side effects that might be attributed to TM-601. Many adverse reactions, including fever, chills, weakness and in one case, seizures, were typical of brain cancer patients.

By all accounts, the radiation therapy, with its effect apparently magnified by TM-601, helped prolong the lives of some patients. Patients in the trial, which did not include a control group because it was considered a "compassionate" use of an experimental drug, had a life expectancy of about three months.

The median survival rate, after administration of TM-601, was seven months. And two patients -- both women in their early 40s -- were still alive almost three years later. In several cases, researchers watched their subjects' tumor growth slow and even stop, buying these patients a few more months of life without the toxic side effects of some cancer therapies.

Although TM-601 may not be the magic bullet patients would like to see, researchers are cautiously optimistic about its prospects. "The responses are intriguing," the authors wrote.

Mamelak, whose study was sponsored by Transmolecular Industries but who has no direct financial stake in the company, cautioned that nothing in the study suggests that TM-601 will be a miracle drug. But its safety, precision and seeming effectiveness in prolonging life may move it toward testing on wider populations of patients, he said.

Mamelak said Phase II studies aimed at testing the safety of varying doses of TM-601 have begun. Future trials, he said, would test whether TM-601 will seek out and bind to other kinds of malignancies as powerfully as it does to gliomas. Lab and animal studies done to date strongly suggest it will, he said.

"It's likely to be equally, if not more effective" on other malignancies, including lymphomas, melanomas, non-small-cell lung cancer and sarcomas, Mamelak said. In lab studies, scorpion venom has also shown a knack for seeking out and binding only to cancerous tissues, leaving surrounding healthy tissue alone.

Melissa Healy writes for the Los Angeles Times

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