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09/30/91

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SAVE A TREE OR SAVE A LIFE

STANFORD--A tree took Audrey Avansino's mind off her cancer--a magnificent tree on the shore of the Mokelumne river that attracted hawks, deer and goats. In her mind Avansino joined the animals in the tranquil setting. She watched the tree from a comfortable couch in the home of a friend and was distracted from the pain and fear of her chemotherapy treatment.

While she occupied her mind with one tree, another tree was responsible for a powerful drug racing through her blood vessels, trapping cancer cells lurking in her body.

Avansino, who is recovering from advanced ovarian cancer, was the first patient at Stanford University Medical Center to receive the experimental drug taxol, a substance found in the bark of the Pacific yew tree.

High level officials at the National Cancer Institute (NCI)-- characteristically cautious and tempered--are calling taxol the most exciting new anticancer drug in 15 to 20 years. In early clinical studies, patients with advanced ovarian cancer who failed to respond to standard therapies have reportedly shown a remarkable 35 percent response rate to the drug. A first trial of the drug in breast cancer patients has been effective in almost half. The NCI is eager to continue testing the drug for at least 10 different cancers.

But even with all the excitement, few people in the United States have been given taxol to treat their cancers. Why?

About six 100-year-old yew trees must be sacrificed to treat each cancer patient. But the scraggly, slow-growing Pacific yew, once common in old-growth forests from Northern California through British Columbia, has fallen victim to widespread clear-cutting, making it scarce. Environmentalists are fighting to limit the number of yew trees cut down each year because large-scale cutting of the yews threatens forests, the endangered Northern spotted owl and other wildlife that live there.

The conflict seems impossible. Thousands of people's lives might be helped by the drug if more trees could be cut, but the forests must be maintained if the environment is to be preserved, the owls are to survive and the supply of taxol is to last. And, conservationists argue, who knows what other wonder drugs may lie still undiscovered within the forests?

Many enthusiastic researchers believe the feud between patients and environmentalists will eventually subside. They are combing the planet for other types of yew that produce taxol in greater abundance than taxus brevifolia--the Pacific yew. They are working on a variety of methods for making the drug in the laboratory using parts of the tree that can be harvested without killing it, such as the dark green, flat needles that are the trees' leaves. And, they are challenging themselves to recreate the extremely complex chemical structure of taxol from scratch without touching any trees at all.

Ovarian cancer, one of the first cancers in which taxol showed promise, has proven extremely difficult to treat. Part of the reason ovarian cancer kills 12,500 women each year is that it is rarely detected in its early stages. In all her 66 years, Avansino had been healthy and active, receiving yearly check-ups. The only time she had ever been admitted to a hospital was to give birth to her twin sons.

Then late last year Avansino noticed a lump near her waist. She and her doctors thought it was a hernia and planned to put off surgery until after the hectic holiday season. Avansino thought it was her imagination, but when it seemed that the lump was growing she was anxious to have it taken care of and arranged for an earlier appointment.

A biopsy proved her right, and she learned the bad news two days before Christmas. Cancer that had originated in her ovaries was growing. Avansino was referred to Stanford gynecologic cancer specialist Dr. Nelson Teng. "He operated on me on Jan. 3," she recalls, "so I knew it was bad. There wasn't much time."

Teng removed a large tumor from Avansino's abdomen but, because her cancer was at such an advanced stage, the probability was high that some cancer cells had broken away from the tumor and were floating through her body, looking for new areas to attack. Because ovarian cancer often goes undetected until such a late stage, chemotherapy is a routine follow-up to surgery. Still, most patients die of the disease.

Teng told Avansino about the taxol clinical trial before she left the hospital. She agreed to participate and was selected to receive taxol instead of the standard follow-up drug treatment. Three months later, during her fifth of six treatments, she chatted about her thoughts and experience while the drug dripped slowly into her left arm.

"There's quite a history behind the yew tree," Avansino noted. "Shakespeare refers to it in some of his writings. It's always the yew trees around the cemeteries in England. In Greece I think they used to make poison out of it to get rid of people they didn't want around. As long as it poisons the cancer--that's what I'm after."

Although she admits dealing with the cancer has been a nightmare at times, Avansino maintains a positive outlook. When told she was to receive her latest treatment in what she called a "claustrophobic room," she persisted until space was found in a room with a window--and a view of a tree.

Avansino's treatment combines one day of taxol followed by one day of a standard anticancer drug called cisplatin. The cisplatin leaves her feeling lousy, but she suffers no side effects on the day she receives taxol. Unlike many cancer drugs, taxol does not work by killing cells. It binds to microtubules, components found inside the cell. These ubiquitous elements make up the cell's skeleton and are involved in cell division, movement and transport of molecules within the cell. Microtubules are always busy assembling and disassembling themselves, and taxol works by latching on and paralyzing them. By interfering with the activities of microtubules, taxol prevents cancer cells from growing and functioning normally.

"Taxol doesn't stop the cell from doing anything but proliferating," explains Stanford chemistry professor Paul Wender, who is working to synthesize taxol in the laboratory. "That's the key. If it gets into a normal cell, no problem. If it gets into a cancer cell, it's not going to kill the cell, it's just going to stop it from multiplying. The biggest problem with cancer is not necessarily that you have transformed cells. Rather, it's the unchecked, uncontrolled proliferation of these cells."

A single transformed cell that's on the way to forming a tumor takes between 25 and 30 doublings of the cell population--one cell will multiply to make two cells, those two will give four, those four will give eight and so on--to reach a size that would be detected by a physician, Wender says. Only 10 additional doublings may be required before the tumor becomes deadly.

"The smallest detectable amount is already three quarters along the way to a lethal size for many types of tumors. If we can slow down the proliferation and come up with better ways of detecting tumors, that will be great."

Avansino isn't the only ovarian cancer patient enrolled in the taxol study at Stanford, but as of a few months ago she was the only one receiving the drug. After studies of a drug's toxicity and efficacy are done, a trial such as this--known as a Phase III trial--is planned to compare the experimental treatment to the best known treatment currently available.

"Any drug that has not gone through carefully controlled clinical trials just offers clinical impressions. Often these don't pan out," Teng says. "The only way to determine the value of a drug is through clinical trials."

One month after completing her taxol treatments, Avansino was "doing great," he says. He was preparing to do "second look" surgery to make sure there wasn't any tumor left, but he has reason for optimism. CT scans and blood tests indicate that the six taxol/cisplatin treatments have left no cancer behind.

But even in the midst of promising results from his first taxol case, Teng is cautious. "I want to emphasize that this is not the panacea of cure. It is just one of many drugs we are testing."

Wender agrees. "It would be terrible if people were to be encouraged to believe that there is some kind of major league cure coming on line that didn't materialize."

It will be at least a year before the Stanford clinical trial using taxol against ovarian cancer is complete. Many other drugs are being tested as well. "Taxol isn't the be all and end all in chemotherapy," says Stanford oncologist Dr. Branimir Sikic. "Hopefully it will be one of several drugs to treat people."

Taxol is not even unique in the fact that it originates from a plant. At least 10 anticancer drugs derived from natural products are currently commercially available or in the late stages of clinical trials. And, according to a recent article by Sikic, the NCI continues to search for new natural products from unexplored marine and tropical sources. "The diverse and complex structures and mechanisms of natural products in pharmacology are likely to continue to transcend the imagination of human chemists."

Michael Friedman, associate director for NCI's Cancer Therapy Evaluation Program, has predicted that an adequate amount of taxol to treat all potentially eligible patients with ovarian and breast cancer won't be available for the next one to two years.

Right now, the NCI only offers taxol to patients participating in clinical studies. This year, enough of the drug will be produced to treat only a few hundred of the 70,000 to 100,000 who could potentially benefit from the drug. Efforts are underway to determine specifically which patients are most likely to respond to the drug so that it can be appropriately conserved until it is more readily available.

But as awareness of the drug grows, so does the frustration of those who are denied access. Earlier this year, 500 pounds of yew bark were illegally stripped--apparently by amateurs--from trees in Oregon. The U.S. Forest Service and USDA have authorized only one company to collect and process the bark, and this exclusive arrangement has caused a stir among environmentalists who claim the company's harvesting methods waste bark as well as among politicians who claim the deal will prevent other companies from doing research on the drug.

Moving from the forest into the lab to look for taxol sources seems the only solution.

Researchers have known about taxol for some time. As part of an NCI-sponsored large scale plant screening program, taxus brevifolia was harvested for the first time in 1961. The crude extract from the tree indicated that there was something of biological interest, but it took 10 years for scientists to arrive at the structure of taxol.

Chemists were intrigued because taxol had some significant structural features that had never been seen in other types of molecules before. "It presented unsolved problems for which synthetic chemists tried to develop solutions," says Wender, who became interested in taxol in the early 1980s. To him the challenge was figuring out how to make the extremely complicated taxol molecule in the laboratory.

Then, in the late 1980s, scientists started getting a better definition of taxol's biological activity and, only during the last two years has taxol begun to look promising for human use.

When taxol showed promise in treating ovarian cancer, Wender got the message that it was going to be necessary to produce it in large quantities. "We decided that we had to respond in a timely fashion. It was no longer a matter of just seeing if we could sort out the problem. We had to see if we could sort it our within a time frame that would be meaningful for the people who need this compound."

In March of 1989, Wender told graduate student Tom Mucciaro that, in his mind, there was no more important target for them than to develop a viable process for synthesizing taxol. They set two major conditions for the effort. First, they would work on taxol in the lab only if they could develop a concept for a practical synthesis. In addition, the process they came up with had to be cost-effective and efficient so that people could actually use the compound.

"It's not unlike climbing Mount Everest," Wender says. "There's something about making it to the top, but the challenge we have is much more than just being able to plant the flag on the summit. We have to get a few hundred thousand people up that summit every year."

At a time when other groups were throwing up their hands, claiming the taxol structure is too complicated to replicate, Wender and Mucciaro brainstormed until they were convinced that they had a reasonable approach to test in the lab. It wasn't easy. "Things were despairing at times until we managed to pull it out toward the end of last year and establish that we had the potential of solving this problem at a practical level."

Up from one graduate student at the beginning of the year, Wender now has five people in his lab working on taxol. He could double his staff before the year's end. They have happened upon a starting material that is "as available as potting soil," and five chemical operations later they can produce the core subunit of taxol.

"There's a lot more to do beyond that," Wender cautions. If his group can produce the whole taxol compound of 15 to 25 additional steps, they will have a practical process for synthetically producing taxol. "If you have to go to 35 or 40 steps, then forget it. It would not be cost effective."

In addition, Wender says, as his team continues to add to the taxol skeleton, it is likely they will find that some components behave much like the whole taxol compound. "Nature didn't have taxus brevifolia produce taxol to fight human cancers. It presumably has other functions in a tree and not all of its complex skeleton is necessary for the anti-cancer activity. If we could find just that special subunit of taxol that's required, that would greatly simplify synthesis."

Another promising laboratory-based approach is the development of a compound closely related to taxol, called baccatin, which is produced in the leaves of taxus baccata, the English yew. Researchers at Florida State University have found that baccatin can be converted to taxol in a half dozen or more steps, and they have been granted a patent for the process.

"It's not produced in high abundance and you still have to do some synthetic work," Wender says, "but this promises to be a good source of taxol once we find out how to produce more of it in the leaves and to do the synthesis more efficiently." The approach is attractive because the tree does not have to be sacrificed. Baccatin is extracted from clippings, purified and then synthesized into taxol.

Scientists also are hoping to learn how nature produces molecules like taxol. "We could hitch-hike on nature's inspiration, sending in very simple starting materials--which is what nature takes from the soil--and converting them into complex molecules like taxol using catalysts," Wender says. "That is a longer term prospect, but it's exciting and would require a lot of collaboration between the biochemical community and the molecular biological community."

In another approach, cells capable of producing taxol are grown in a culturing medium that allows them to proliferate. Among several groups developing such tissue culture approaches, a local company, ESCAgenetics Corporation of San Carlos, recently reported successfully producing a tiny quantity of taxol through a proprietary plant tissue culture technology. Claiming to be able to produce the substance at levels greater than those found in the bark and needles of the yew, the company is hoping to "scale up to commercial production within the next two years."

"I've never seen scientists more excited about something than this taxol problem," says Wender, who recently chaired an NCI- sponsored request for applications that brought together researchers studying taxol from every angle. "Everybody is bristling with enthusiasm and with hope.

"If you take the efforts of scientists out of the picture, it looks like a no-win situation. You have humans and human life on the one hand and you have our environment and endangered species and industry on the other hand. This is not necessarily solvable if you only consider those two options.

"But if you consider the other options of producing this either in the laboratory through synthesis or special types of tissue culture techniques, or molecular biological techniques, then hopefully we can do away with that controversy."

Avansino, understandably concerned more with her own struggle than the broader controversy, faced her second-look surgery with mixed feelings two months ago. Two days before making the trip from Stockton to Stanford, she said she was encouraged that tests predicted everything was fine, but she still dreaded the surgery, the week in the hospital and the possibility of one to three more chemotherapy treatments "just as a safety precaution."

"It's sort of like being half way across the river," she says. "You can't turn back, so you may as well keep going."

After leaving the hospital, Avansino will recuperate at her friend's home in Lodi, on the shore of the Mokelumne river. Only time will prove whether the taxol has really beaten her cancer. For relief from the worry, Avansino can mentally escape to the comforting tree that is home to local wildlife, hoping that another tree has given life to her.

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