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MEDICINE | IN THE LAB

Venom as a natural defense

Potent toxins that prove deadly when a scorpion stings may be tomorrow's `smart weapons' against cancer.

August 28, 2006|Melissa Healy | Special to The Times

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 four-inch arthropod the name deathstalker scorpion may be the key to longer life for humans under attack from an even more insidious predator.

In a study published in the August 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 later 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 long overdue. Of the 17,000 Americans diagnosed each year with glioma, fewer than 1 in 10 live 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 Transmolecular 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, allowing it to reach cancerous brain tissue.

In the Journal of Clinical Oncology, researchers led by Cedars-Sinai 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, following 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.

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