Will Taxol Hunt Result in A Cancer Cure?

More than two decades ago, in 1971, a hubbub of scientific inquiry surrounded a rare strain of yew tree in the Pacific Northwest.

It seemed that taxol, a drug which would soon be used successfully to shrink ovarian and breast cancer tumors, was only found in the bark of the rare tree.

And today, while it has not yet been approved by the Food and Drug Administration as a first-line treatment for cancer, taxol is now used as a backup therapy if conventional platinum-based chemotherapy fails, according to Dr. Ross Berkowitz, professor of gynecology at the Medical School.

Berkowitz, who works at Brigham and Women's Hospital and the Dana Farber Cancer Institute, says that about 20 percent of patients in which chemotherapy has failed show improvement after taxol treatment.

"[Platinum-based chemotherapy] is agreed to be the best single active drug in treating ovarian cancer," he says. "It is generally agreed upon that taxol is a reasonable second line therapy."

But the giving capacity of what an article in Audobon called the "tree of life" is somewhat limited. According to the American Cancer Society, treatment of one patient requires about three mature trees worth of bark. And such treatment often leads to side effects similar to those suffered by chemotherapy patients, including nausea, vomiting, depression of blood count and cardiac problems.

Frustrated by the scarcity and of the drug, scientists, including Professor of Chemistry Eric N. Jacobsen, have attempted to develop synthetic forms of taxol. Jacobsen's work centers on finding a natural product which can be modified to taxol. Recently, the chemist successfully synthesized taxol from a compound known as diterpene, obtainable in large quantities from nature.

Instead of synthesizing taxol itself, other researchers are attempting to synthesize drugs similar to taxol which may be even more effective against cancer--without the side effects.

For example, Iwo Ojima, professor of chemistry at the State University of New York at Stonybrook, is working on an analog to taxotere, a compound similar to taxol, known as Baccatin III. Taxotere, another drug with taxol's properties extracted from the leaves of the European and Indian yew trees, is more widely available than taxol and can be produced in greater quantities.

The disadvantage of taxotere, however, is that it also causes the side effects of taxol. Baccatin III, says Ojima, may grant doctors the best of both worlds by eliminating both taxol's scarcity and its side effects.

"Our aim is to reduce those side effects and make a drug that is easier on the patients," says Ojima. "We are working on a structure activity relationship study and focusing on the new baccatin."

Although trials of the drug are still in their early stages, Ojima says some of the baccatin compounds have already been shown to have a greater effect on tumors than taxol. The compound also dissolves better in water, so it may be easier to administer.

With the increased availability of taxol which the work of Jacobsen, Ojima and others might bring, many oncologists are using it to treat patients with ovarian and breast cancer.

But physicians caution that taxol is not a cancer cure. "I've been giving it to patients who won't be cured by it," says Dr. Louis J. Ayash, an instructor in medicine at the Medical School. "It will never clearly get rid of the tumor."

Rather, says ovarian cancer specialist Dr. Steven A. Cannistra, assistant professor of medicine at the Medical School, taxol represents a different kind of treatment which could prove effective after other chemical agents fail to induce responses in patients who have developed a resistance to platinum.

"Many patients with platinum resistance are still sensitive to taxol," he says, "so we use it for patients who have this resistance or who develop a relapse right after the platinum-based treatment."

Ongoing studies by Cannistra and researchers around the country are, however, testing the effectiveness of taxol as a possible first-line therapy. And initial results seem promising.

Cannistra says the results of the trial indicate that the response rate to the taxol-containing treatment is 79 percent, while that to the standard non-taxol treatment is 63 percent.

"Because of that difference," says Cannistra, "we think that taxol may play a more important role in the treatment of newly diagnosed patients. Whether increased responsiveness will overall translate into better survival will require long term results."

At this time, the FDA has only approved taxol for treatment of ovarian cancers after other treatments have failed. But at least one physician hopes this will change.

"I think it should be used as first line, but it is very expensive and supplies are limited," says Dr. Mussa Banisadre, medical director of the California Cancer Center. "Within the next few years we'll see taxol as a first-line treatment for breast cancer, but I don't think it will be used as a first-line treatment for ovarian cancer."

Even were taxol to become a first-line treatment, scientists concede that it would be better used in combination with other anti-cancer drugs. "I don't think anyone will ever use [taxol] alone knowing that the combination chemotherapy is the only way patients have been cured," says Ayash.

"Our experience shows that whenever you use a single drug it's not as effective as if you combine it with other active drugs," agrees Banisadre. "Eventually resistance develops because not every cancer cell behaves the same as the next one."

With all the information provided by recent studies, Jacobsen says the hope and optimism regarding taxol has decreased significantly since its first isolation in 1971.

"It was once considered a wonder drug," he says. "Now people are more calm about the prospects because some of the trials that have come back indicate that taxol is not as effective as once thought."

Scientists, says Jacobsen, will need to take advantage of what nature has inadvertently given them.

"This is a molecule that a tree makes," says Jacobsen. "A tree isn't trying to cure ovarian cancer, but it has given us a great clue as to what might work."