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February 7, 2007

Toxin From Sea Creature Could Lead To Promising Cancer Treatment

Topics: Medicine

Back in 1990, most divers would have ignored the four-by-six-inch, cream-colored, jellylike mass clinging to an underwater cliff off the coast of the Philippines. After all, it hardly even looked like an animal. Nevertheless, a team of American and Filipino scuba-diving researchers collected about half a pound of it, back in 1990. From this small store, they extracted less than a thimbleful of a chemical substance. Studies showed that it killed cancer cells in a test tube, but the scientists needed more of it to assess its potential as a drug in human patients. They returned to the Philippines several times, but it took eight years to find the animal again. - from ScienceNotes 2002.

What began in 1990 with the collection of a few specimens, culminated with scientists extracting a tiny amount of a toxin, diazonamide A, which the animal probably uses to repel predators. The toxin proved to kill cancer cells in culture, but so little of its natural form was available that a race soon began to synthesize it in the laboratory. Finally a variant of diazonamide A, called AB-5, was synthesized. AB-5 has a structure nearly identical to diazonamide A and is indistinguishable in its biological action, but is easier to synthesize in the lab.

molecule72.jpg

Now, AB-5, the variant of the toxin derived from Diazona angulata that was first discovered in 1990 by divers in the Philippines, has been proven in a study by UT Southwestern scientists to block uninhibited reproduction of cultured human cancer cells while leaving healthy cells unaffected:

... in pre-clinical trials, a synthetic form of the toxin (AB-5) reduced human tumors implanted in mice without the harmful side effects seen using other cancer drugs. "Diazonamide is a special molecule - it's teaching us more than we imagined," said Dr. Patrick Harran, professor of biochemistry and a senior author on both studies.

"This is a truly exciting result," said Dr. John Schwab, a program officer at the National Insti tutes of Health's National Institute of General Medical Sciences, which partly funded the work. "Not only has this UT Southwestern team identified a potent anti-cancer drug, but its unique mode of action avoids the kinds of side effects that make cancer chemotherapy so difficult. It's a great example of how NIH support for fundamental chemical research can benefit the American health-care consumer."

The animal, Diazona angulata, is a sea squirt a few inches wide that lives in colonies anchored to rocks. It was discovered offshore of the Philippines in 1990 as scientists were looking for species that might lead to useful drugs. From a few specimens, scientists extracted a tiny amount of a toxin, diazonamide A, which the animal probably uses to repel predators.

The toxin proved to kill cancer cells in culture, but so little of its natural form was available that a race soon began to synthesize it in the laboratory.

A chemical structure for diazonamide A was published in 1991, but in 2001, Dr. Harran's group showed that initial report to be incorrect, and uncovered the correct structure. In the first of the two new studies, Dr. Harran and his co-workers synthesized several variants of diazonamide A in order to pin down how it prevents cancer cells from dividing.

Normal cell division involves a structure called the mitotic spindle, which pulls apart the chromosomes before the cell splits. The spindle is primarily made out of a substance called tubulin. Some anti-cancer drugs attack tubulin, but they have serious side effects, such as nerve damage and depletion of bone marrow and white blood cells.

The UT Southwestern researchers found that while diazonamide A blocked cell division, it seemed not to bind directly to tubulin. Instead, Dr. Xiaodong Wang, professor of biochemistry, and Dr. Gelin Wang, instructor of biochemistry, found that the toxin interacted with an enzyme called OAT, which was known to be involved in cellular metabolism but had no previously known role in cell division.

Interestingly, diazonamide did not block OAT's enzyme activity, the researchers said. Rather, it uncovered a second function for the protein in cell division.

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Posted by Richard at February 7, 2007 12:21 PM



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