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Unlocking the secrets of taxol.

Dr. Robert Holton and his chemistry colleagues at Florida State University stood in a circle, their mouths open in astonishment., staring at a reaction vessel. Inside the vessel they had successfully created a partly synthetic version of a rare cancer-fighting drug that experts are calling the most exciting new chemotherapy in decades.

"We didn't expect it to work so well," admits the 47-year-old chemistry professor about this key experiment in his 20-year quest to synthesize the complex drug called taxol. "That was our ah-hah moment, when we broke open the champagne."

The race to create taxol has grown heated over the last few years as National Cancer Institute studies with the drug have demonstrated a striking 30 percent to 40 percent response rate in advanced cases of ovarian cancer. In addition to helping women whose ovarian cancer did not respond to any other treatment, taxol also has shown significant tumor shrinkage in breast cancer and is being studied on numerous other kinds of malignancies including lung and colon cancer, says NCI'S Saul Schepartz, an expert in developing anti-cancer therapies.

"But experiments have been limited by the scarcity of the drug," Schepartz notes, "since it is derived from the bark of a rare yew tree."

The ecological dilemma posed by sacrificing rare trees to save human lives is one reason why Dr. Holton's process is being heralded with such promise. Up until now, taxol has been available only in small amounts from the bark of Pacific yew trees, which are sparsely sprinkled through forests in the Pacific Northwest. In a clash that one NCI official called "the ultimate confrontation between medicine and the environment," extracting taxol for experimentation has meant destroying the rare trees that also provide a home for the endangered Northern spotted owl.

Six 100-year-old trees must be stripped of their bark to provide enough of the drug to treat a single patient. Fewer than 1,000 patients can be treated this year with the amount of taxol now available, the New York Times reported in May.

"Our concern is that we not kill the goose that lays the golden egg," Wendell Wood of the Oregon Natural Resources Council told the Wall Street Journal in April. "This is a finite resource. Ancient forests that gave us the yew may give us answers to medical problems we haven't thought to ask."

Dr. Holton's patented processes solve several of these problems.

"First, we used the needles to extract the drug, not the bark," he says. "This means that you don't need to kill the trees, since needles grow back. It involves, basically, clipping shrubbery.

"Second, we used the English yew, which is a common ornamental shrub, instead of the rare Pacific yew."

Dr. Holton's process involves joining a compound called Baccatin III--which is a major component of taxol--with an easily-synthesized side chain. Coupling these two-creates taxol. Baccatin III is most abundant in the leaves of the English yew, notes Holten, who says his process requires about two pounds of English yew needles to derive enough Baccatin III to produce taxol for one patient.

But the quest isn't over yet.

"Nothing's won until taxol's out there and available to patients," says Holton. "The big question now is how do you get large quantities of Baccatin III?"

Currently, he says, Bristol-myers Squibb Company--which has a licensing agreement with the university to use the taxol process--is combing the world to uncover the best plants and best processes for extracting Baccatin III. Holton and other scientists are also working to synthesize Baccatin III, but for now he says the hundreds of varieties of yew are more likely to be the best source.

"We're currently investigating alternative sources to the Pacific yew to evaluate how much taxol and taxol-like compounds are in other kinds of yews," says botanist Ed Croom of the University of Mississippi. "A nursery can produce millions of ornamental yews to give us a sustainable base."

Scientists also are studying taxol to see how it works, and, in the process, learn more about cancer, too. Discovered 30 years ago as part of an NCI program to collect and identify plants with anti-cancer action, taxol kills cells in a way that researchers have never seen before.

"Taxol works by blocking cells just when they are going to divide, so it inhibits the replication of cells," says Susan Horwitz, professor of molecular pharmacology at Albert Einstein College of Medicine, who in 1979 discovered the unique way the drug acts. "Taxol binds to microtubules in the cell so they can't form spindles" necessary to replicate, Horwitz says.

Two things about taxol sparked her interest in studying the drug. "First, the chemical structure is unusual and previously hadn't been looked at in terms of its biological action," Dr. Horwitz says. "This is a very complex chemical with a structure that only a tree could make.

"Second, we knew from work at NCI that taxol had increased the survival time of mice with cancer."

Taxol's unique structure also caused Holton to devote a good part of his career to unlocking its secrets.

"When I first saw taxol's structure, back when it was isolated in 1971, it was so unusual and complicated that one could hardly even believe it exists," says Holton, who at that time was doing post-doctoral work at Stanford. "It's fantastically structurally challenging . . . the way the carbon atoms are connected, their size and shape and so on, involved a number of questions that had not been addressed before. It was clearly a problem one could sink one's teeth into."

Holton broke the problem of synthesis into several steps. In 1984 his laboratory successfully constructed the tricyclic taxane ring system. In 1988, they synthesized taxusin, a naturally-occurring compound that contains the entire ring skeleton of taxol. A year later, they created taxol by combining Baccatin Ill with a synthesized side chain. Now they are working on creating a totally synthetic form of Baccatin Ill and taxol.

In the meantime, others are focusing their attention on the yew tree--which for years was burned by lumber companies who regarded the plant as a weed. Both slow growing and long lived, the yew has interesting historical associations.

In medieval times, every parish in England was required to provide a quota of bows made from the yew because of the flexibility of its wood. Since the leaves and berries are poisonous, the tree was grown in fenced churchyards to protect grazing animals.

Although it may be two or three years before taxol can be produced in large quantities, these trees and bushes, whose foliage can bring death, are already bringing hope to the many thousands of Americans who struggle with ovarian cancer.
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Title Annotation:anti-cancer drug
Author:Krucoff, Carol
Publication:Saturday Evening Post
Date:Sep 1, 1991
Words:1111
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