Venom as a natural defense
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.
Mamelak, whose study was sponsored by Transmolecular Industries but who has no direct financial stake in the company, cautioned that nothing in the current 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.
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Snake cures that aren’t snake oil?
Fans of nature TV know the feeling: They just can’t look away as the predator -- slithery, spiny, stealthy or starving -- pounces upon an unsuspecting food source. The hunter fells its prey, which is often bigger and smarter, not with brute power but with surgical precision. Its venom paralyzes or disrupts some vital function, crippling the victim. Evolution picks the craftiest, and the predator has its way with its helpless prey.
Medical researchers are transfixed as well. The powers of certain venoms -- or of components within them -- offer possibilities to dull the sensitivity of nerves, alter the flow of blood through arteries and veins, knock down cell walls and attack the virus within. As a result, toxins that occur naturally have become a hot subject of drug discovery in recent years.
The toxin that the cone snail uses to paralyze its prey has produced one drug, an analgesic called ziconotide, which treats neuropathic pain that morphine fails to blunt. ACE inhibitors as a treatment for heart disease emerged from research on snake venoms. And cobra venom that dissolves virus cell walls and membranes has been used for years in medical research.
Venom works in ways as diverse as the combinations of predator and prey in nature. But virtually all fall into two categories -- neurotoxins, which act on the nervous system, and hemotoxins, which target the blood flow. The venom of cobras, mambas, sea snakes and coral snakes are neurotoxins. Rattlesnakes, copperheads and cottonmouths kill their prey with hemotoxins. Some venoms have both properties.
And some, such as chlorotoxin in scorpion venom, disrupt the chemistry that allows cells to communicate with each other, causing those cells to misfire or die.
Research today is focused on synthetically produced drugs that mimic the effect of naturally occurring venoms.
The Malayan pit viper’s venom is thought to have a powerful anticoagulant effect that could become part of stroke therapies. A component in the venom of the Brazilian arrowhead viper is thought to prevent the constriction of blood vessels, making it a possible blood pressure drug. Other proteins in snake venom are being used to investigate how receptors of certain brain cells respond to nicotine and other addictive substances.
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