Taxol

Taxol^® becomes a drug

In August 1978 Monroe Wall received a letter from John Douros, who had replaced Jonathan Hartwell at the CCNSC, that read: “Dear Monroe: Can you help this poor girl?” Attached was a letter from Susan Horwitz asking for some radiolabeled Taxol® to conduct experiments on its mechanism of action. Like many researchers, Horwitz, a molecular pharmacologist in the Albert Einstein College of Medicine at New York’s Yeshiva University, had been hearing reports about Taxol®. She had managed to obtain a few milligrams of the substance, which she used to kill cancer cells growing in a culture. Determined to find out how it worked, Horwitz pressured NCI to get her more Taxol®.

Supply remained a problem. In July 1977 Matthew Suffness of the NCI placed an order with the USDA for 7,000 pounds of bark, which meant killing about 1,500 trees. Such a large order attracted the attention of environmentalists who began to wonder about the government’s sudden interest in the Pacific yew, long considered a “trash tree.” To environmentalists the tree, scattered in patches hidden within millions of acres, had a place in the virginal, old-growth forests of the Pacific Northwest. Environmentalists feared a massive attack on the Pacific yew would spell ecological disaster for the region. In the next decade this fear became enmeshed in the debate over the northern spotted owl, which lived in the forests of the Pacific Northwest and which the federal government eventually declared threatened.

Horwitz was able to get enough Taxol® to run tests that revealed its lethal secret, which turned out to be a mechanism completely new to scientists. Previous compounds killed cancer cells by inhibiting their division; they did this by preventing the production of ultra-fine filaments called microtubules that enable cells to divide. Cells manufacture millions of microtubules and use them as building blocks for a new cell. When a new cell breaks off, the microtubules become fragments of the protein tubulin. Before Taxol® anticancer agents worked by inhibiting the polymerization of tubulin to form microtubules; hence, the cells could not divide.

Horwitz discovered that Taxol® worked differently. Instead of preventing the formation of microtubules, it stimulated their development. Cells treated with Taxol® begin churning out so many microtubules that they are unable to coordinate cell division. As a result, cells die of continued attempts to replicate their DNA in the absence of the ability to divide.

Armed with this information, Suffness at NCI was able to argue that, because of its unique structure AND mechanism of action, Taxol® was a candidate for further development. Buttressing that argument was Taxol’s® success in causing regression in the mammary tumor xenograft. Suddenly, Taxol® was “hot,” with some seeing it as a potential “miracle drug.”

Then came a disastrous discovery: Taxol® is virtually insoluble in water. No matter how good Taxol® was shown to be, if it could not be added to a medium so that it could be administered intravenously, it was worthless. Without any way of getting Taxol® into a patient, clinical trials could not begin. But after a year of looking, the NCI drug formulation team found that Taxol® dissolved in a special elixir made of castor oil and marketed as Cremophor EL. This paved the way for Taxol® to move into clinical trials on humans.

Taxol® progressed fairly smoothly through clinical Phase I and Phase II trials, once patients were premedicated to suppress severe allergic reactions to Cremophor EL. In fact, the results of Phase II trials against refractory ovarian cancer showed a previously unheard of response rate of thirty percent. The clamor about Taxol® intensified, forcing NCI to do the math. If Taxol® were made available to all victims of ovarian cancer, the institute would have to produce 240 pounds of the drug. That would mean killing 360,000 Pacific yews. It did not take a mathematical prodigy to understand that this was an equation without a future.

The numbers encouraged scientists to search for a synthesis, to in effect short cut nature. The first success story came in France, where Pierre Potier looked at a semi-synthesis. From the needles of the ubiquitous Taxus baccata, or English yew, Potier extracted 10-deacetylbaccatin III, commonly known as 10-DAB. The English yew is loaded with this compound, which contains the complex core of Taxol® minus the relatively simple side chain. Most importantly, 10-DAB comes from the needles, a renewable resource. After several years of trying, Potier and his colleagues succeeded in marrying 10-DAB to a synthetic version of the tail to achieve a semi-synthesis of Taxol®. This accomplishment led to the development of a plethora of semi-synthetic versions of Taxol®. Eventually, Robert Holton and colleagues at Florida State University developed a commercially viable semi-synthetic procedure.

With the clinical trials going well the NCI began to look for a pharmaceutical company willing to take a chance on turning Taxol® into a marketable drug. In August 1989 the institute advertised that it had a Cooperative Research and Development Agreement (CRADA) to issue to the company with the best proposal. Later in the year, the grant went to Bristol-Myers, soon to merge with Squibb, another giant in the field. Bristol-Myers Squibb worked out a deal with Holton under which it agreed to use his semi-synthetic process for the production of Taxol®.

In December 1992, thirty years after USDA botanists first sampled Taxus brevifolia in a Washington State forest, and more than twenty years after Wall and Wani reported the isolation and structure of Taxol®, the Food and Drug Administration granted approval for Taxol’s® use against refractory ovarian cancer. It has since been approved for use in the treatment of breast cancer and AIDS-related Kaposi’s sarcoma.

In the mid-1990s Monroe Wall and Mansukh Wani wrote of their delight “that their initial discovery… of a novel natural product with excellent activity in a number of animal models has presently reached the stage where taxol is now available in adequate quantity for therapeutic use. Undoubtedly, there are other highly active natural products from plant, marine, and fungal sources as yet unknown which, when discovered, will have therapeutic value. Cancer is not one, but several hundred diseases and will require many different types of agents.”¹

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¹ Wall, Monroe and Mansukh Wani, “Camptothecin and Taxol: Discovery to Clinic,” Cancer Research 55, 1995, p. 759.

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