STRUCTURES OF MARINE TOXINS PROVIDE INSIGHT INTO THEIR EFFECTIVENESS AS CANCER DRUGS

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STRUCTURES OF MARINE TOXINS PROVIDE INSIGHT INTO THEIR EFFECTIVENESS AS CANCER DRUGS
26 September 2005 - University of Wisconsin-Madison

Vibrantly colored creatures from the depths of the South Pacific Ocean harbor toxins that potentially can act as powerful anti-cancer drugs, according to research findings from University of Wisconsin-Madison biochemists and their Italian colleagues.

The research team has defined the structure of the toxins and provided a basic understanding that can be used to synthesize pharmaceuticals, according to a study published this week in the Proceedings of the National Academy of Sciences.

"We've determined how this class of toxins interacts with actin," an important protein responsible for cellular structure and movement, says Ivan Rayment, a professor of biochemistry in the College of Agricultural and Life Sciences who worked with John Allingham, a postdoctoral fellow, on the study. "We're adding to fundamental understanding which will be taken up by others to simplify chemical synthesis of what could potentially be powerful cancer treatments."

The toxins, which are produced naturally by organisms that exist symbiotically on deep-sea sponges, work by disrupting the activity of actin, an abundant protein that gives structure to eukaryotic cells. "Actin forms long chains, or filaments, that are essential for cellular locomotion, division and growth," explains Allingham. "Because cancer cell masses grow faster than other cells in the body, actin provides an excellent target for drugs that could inhibit such rapid growth."

Adds Allingham: "These marine toxins can knock out the lynchpins in these long chains or cap their ends and kill cancer cells. Moreover, initial work shows that even a low dose of these toxins can bring a significant response."

Prior to the study published in PNAS, it was known that the marine toxins affect several forms of cancer, but not how they worked, says Rayment. The recent findings will enable the toxins to be synthesized in a lab instead of harvested from the depths of the ocean floor, meaning that the drugs can be engineered to be as effective as possible. "In order to chemically synthesize a better drug, it is a good idea to know how the natural compound works," he says. "Scientists who study natural products take their cues from what nature has already done. We're adding deep biochemical meaning to this area."

He adds that synthetic chemists hope that actin-based drugs might one day rival the success of Taxol, a powerful drug derived from a natural product that keeps breast-cancer cells from dividing.

"Actin-based drugs have not yet been used as successful drugs as have those that target microtubules, like Taxol, in part because we haven't understood how to target actin," Rayment explains.

Rayment and Allingham collaborated with Angela Zampella and Maria Valeria D'Auria at the Universita degli Studi di Napoli in Naples, Italy. The work was supported in part by a Canadian Institutes of Health Research Fellowship, a grant from the National Institutes of Health and the state of Wisconsin.

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About: University of Wisconsin-Madison
In achievement and prestige, the University of Wisconsin-Madison has long been recognized as one of America’s great universities. A public, land-grant institution, UW-Madison offers a complete spectrum of liberal arts studies, professional programs and student activities. Many of its programs are hailed as world leaders in instruction, research and public service.

The university traces its roots to a clause in the Wisconsin Constitution, which decreed that the state should have a prominent public university. In 1848, Nelson Dewey, Wisconsin’s first governor, signed the act that formally created the university, and its first class, with 17 students, met in a Madison school building on February 5, 1849.

From those humble beginnings, the university has grown into a large, diverse community, with about 40,000 students enrolled each year. These students represent every state in the nation, as well as countries from around the globe, making for a truly international population.

UW-Madison is the oldest and largest campus in the University of Wisconsin System, a statewide network of 13 comprehensive universities, 13 freshman-sophomore transfer colleges and an extension service. One of two doctorate-granting universities in the system, UW-Madison’s specific mission is to provide "a learning environment in which faculty, staff and students can discover, examine critically, preserve and transmit the knowledge, wisdom and values that will help insure the survival of this and future generations and improve the quality of life for all."

The university achieves these ends through innovative programs of research, teaching and public service. Throughout its history, UW-Madison has sought to bring the power of learning into the daily lives of its students through innovations such as residential learning communities and service-learning opportunities. Students also participate freely in research, which has led to life-improving inventions from more fuel-efficient engines to cutting-edge genetic therapies.

Students, faculty and staff are motivated by a tradition known as the "Wisconsin Idea," described by UW President Charles Van Hise in 1904 as the compelling need to carry "the beneficent influence of the university ... to every home in the state." The Wisconsin Idea permeates the university’s work and helps forge close working relationships among university faculty and students and the state’s industries and government.

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