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Scientists Mobilize To Increase Supply of Anticancer Drug Taxol Total and partial synthesis, leaf extraction, tissue culture, and cultivation eyed as potential sources of natural product now obtained only from baric of Pacific yew tree
Stu Borman, C&EN Washington
In ongoing clinical trials sponsored by the National Cancer Institute (NCI), a natural product called taxol has shown promising results in fighting advanced cases of ovarian, breast, and other cancers. However, clinical testing has been slowed because taxol is in very short supply. The shortage of taxol has sparked unusually widespread research efforts, with scientists in medicine, chemistry, and several other fields trying to find ways to increase the drug's availability. Taxol's status as a hot new cancer drug has given researchers an opportunity to help solve a societal problem of pressing importance. After obtaining a patent in May for a partial synthesis of taxol, chemistry professor Robert A. Holton of Florida State University received inquiries from about 100 cancer patients, in addition to numerous stockbrokers, venture capitalists, and reporters. "Cancer patients are literally begging for taxol," says Holton. "As a matter of fact, we've been a bit concerned about security here since we had a fellow get into the building at night and wander around looking for taxol for his mother, who was dying of breast cancer." Taxol for clinical studies is currently obtained by extraction from the bark of the PaBark of Taxus cific yew tree, Taxus brevifolia, brevifolia/ a which grows in forests of the slow-growing western U.S. and Canada. The evergreen, is ground tree is most plentiful on fedand extracted to eral lands in Oregon and produce small amount Washington managed by the of promising U.S. Department of Agriculanticancer drug taxol September 2, 1991 C&EN
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News Focus hire's Forest Service and the Department of Interior's Bureau of Land Management (BLM). It is not a rare plant, but it is not a dominant species either, except in a few locations. Yews are slow-growing evergreens, and the isolation procedure required to obtain taxol is difficult, low-yielding, and expensive. Based on current bark-extraction procedures, NCI estimates that it takes about three trees to provide enough drug to treat one cancer patient. In addition, the trees must be killed to harvest the bark. This has prompted concerns by écologiste about survival of the tree. NCI, BLM, and the Forest Service say they have programs in place to ensure that harvesting of the Pacific yew does not adversely affect its longterm survival or its widespread distribution. At the same time, there is considerable pressure to increase production of taxol because shortages of the drug are holding up clinical trials. If taxol's efficacy against ovarian and breast cancer is confirmed, and if taxol proves active against other types of cancer, the amount needed could increase significantly. The combined potential population of patients with breast and ovarian cancer that could benefit from taxol is 50,000 to 60,000 per year, a number far in excess of the approximately 500 patients currently receiving the drug in clinical trials. Owing to the growing demand for taxol, NCI has made development of the drug an emergency priority. Various means to increase the supply of taxol are the subjects of active research, supported to a large extent by NCI grants and by various cooperative agreements. Strategies being studied include total synthesis (from simple starting materials), partial synthesis (from readily available taxol precursors), extraction from Taxus needles, cultivation of Taxus plants, identification of simpler drug analogs, and cell culture production. Taxol was discovered as part of an NCI-sponsored program in which extracts of over 35,000 plant species were tested for anticancer activity between 1958 and 1980. Working under NCI contract, chemists Monroe E. Wall and M. C. Wani of Research Triangle Institute first isolated a crude taxol concentrate from yew tree bark and wood samples in 1963. Initial screening tests showed the extract to be a potential anticancer agent, and Wall and Wani found the concentrate to be very active against an unusually wide range of rodent cancers. They began work to isolate the active agent in the crude extract, a process that took several years because the agent was present at very low concentrations in the plants. Later, they teamed up with chemistry professor Andrew T. McPhail of Duke University to determine its structure by x-ray analysis, and they named the compound taxol [/. Am. Chem. Soc, 93, 2325 (1971)]. However, says Wall, "Nobody owns the compound. We didn't patent it when we isolated it. I wish we had, but we didn't. We discovered it and put it out in the open literature." Despite taxol's excellent activity in model tumor systems, clinical trials were delayed owing to short supplies of the drug and formulation problems related to its low water solubility. Greater interest in the drug was 12
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Taxol was discovered by Wani (left) and Wall, shown here with structure of camptothecin, another plant antitumor drug, analogs of which are now in clinical trials
sparked by a study in 1979 by Susan B. Horwitz and coworkers in the departments of molecular pharmacology and cell biology at Albert Einstein College of Medicine, Bronx, N.Y. The study found a unique mechanism for taxol's antitumor activity involving cell microtubules. Microtubules play a key role in mitosis, maintenance of cell shape, cell motility, and intracellular transport. They are self-assembling and self-disassembling structures that are in dynamic equilibrium with tubulin dimers, the protein subunits of which they are composed. A substance that interferes with microtubules can disrupt cell growth and function. The 1979 study by Horwitz and coworkers reported that binding of taxol to tubulin acts to stabilize cell microtubules and to prevent their depolymerization. Other drugs were known to bind tubulin, but they all enhanced disassembly of microtubules. Taxol's mechanism was unique. Because tumor cells usually divide much more rapidly than normal cells, taxol inhibits tumor activity. Discovery of the novel mechanism by which taxol disrupts cancer cells intensified research interest in the drug, and NCI began a concerted effort to obtain it for clinical trials. Phase I trials of taxol—aimed at determining the maximum tolerated dose in humans and any dose-limiting toxicities—began in 1983. At first the drug produced some serious hypersensitivity reactions. Researchers soon found that slowing the rate of infusion or premedicating patients with antihistamines and steroids averted such reactions. The major dose-limiting toxicities found in phase I tests were bone marrow suppression and peripheral neuropathy (numbness and tingling of the extremities). Phase II trials—in which a drug's effectiveness is tested on a larger number of patients—are still being conducted for taxol. However, those that have been completed have sparked great excitement among clinicians. A phase II trial of taxol in 1988 by medical research-
ers Eric Κ. Rowinsky, William McGuire, and associates at Johns Hopkins Oncology Center, Baltimore, showed a 30% rate of improvement (combined partial and com plete responses) among patients with advanced ovarian cancer. These were all refractory cases that had not re sponded to standard treatment. Because no response would usually be expected in such cases, a 30% im provement rate is considered quite good. A second phase II taxol study by Gabriel N. Hortobagyi and coworkers at the M. D. Anderson Cancer Center of the University of Texas, Houston, showed tu mor shrinkage in 48% of patients with metastatic (ad vanced) breast cancer whose prior chemotherapy had failed. Taxol also has shown preliminary indications of activity against some other cancers, such as lung cancer and malignant melanoma. Clinicians would like to broaden the scope of taxol trials, but the short supply of the drug has held back such plans. Those who want to conduct phase II tests on taxol must submit applications to NCI and wait their turn in line—a situation that does not lend itself to making rapid progress. Two years ago NCI determined that it would need assistance from the private sector if it were to obtain enough taxol for clinical trials and get the drug ap proved and marketed quickly. The assumption was that clinical trials of taxol would continue to go well, as they have. In January 1991, after a competition in which four drug companies participated, NCI signed a Collabora tive Research & Development Agreement (CRADA) with Bristol-Myers Squibb, making the drug company its partner in taxol development. A CRADA is the in strument used by federal agencies for collaborative re search and technology transfer with the private sector. The taxol CRADA states that, in exchange for exclusive access to detailed NCI clinical and preclinical data, Bris tol-Myers Squibb will provide taxol to NCI for clinical studies and will file and prosecute a new drug applica tion with the Food & Drug Administration to gain mar keting approval. NCI has requested that Bristol-Myers Squibb arrange for the collection of about 750,000 lb of dried T. brevifolia bark (about 38,000 trees) during the 1991 growing sea son. This should yield about 25 kg of pure taxol, enough to treat about 12,000 cancer patients, a considerable in crease over the few hundred patients receiving the drug this year. According to NCI, 25 kg of taxol will be enough to support its highest priority clinical studies and to begin providing taxol on a compassionate basis to cancer patients not participating in clinical trials. To fulfill its commitment to NCI, Bristol-Myers Squibb also has signed cooperative agreements with the Forest Service and BLM granting the company right of first re fusal to Pacific yew harvested on federal lands. Acting as Bristol's agent under these agreements, Hauser Chemical Research, Boulder, Colo., is overseeing collection of yew bark and processing of the bark to extract taxol. BristolMyers Squibb prepares the final dosage formulation and delivers it to NCI for use in clinical studies. Exclusive access to NCI data virtually ensures BristolMyers Squibb a monopoly on taxol, a fact that has
caused some to question the terms of the CRADA. The company also has received orphan drug designation from FDA for specific use of taxol in ovarian cancer cases. This means that when the drug is approved, the company will have seven years' exclusive marketing rights to the drug for that disease. Rep. Ron Wyden (D-Ore.), chairman of the House Small Business Subcommittee on Regulation, Business Opportunities & Energy, held a Congressional hearing on July 29 to express concern over the agreements be tween Bristol-Myers Squibb and federal agencies. Wy den says, "Giving Bristol-Myers Squibb significant tax payer-owned resources to corner the market on an im portant new drug may be a fast way to get taxol to some cancer patients. But . . . in the government's crash ef-
Taxol and Taxotère can be synthesized from precursor
Taxol
Taxotère
10-Deacetylbaccatin III (precursor)
!
Source: David G. I. Kingston, Virginia Polytechnic Institute & State University
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News Focus forts, it cannot close its eyes to potential problems in these agreements." Wyden believes the agreements represent troubling restrictions on the free flow of information from government-funded research and that they fail to protect the public interest. He contends they do not ensure commercial fair play, responsible management of yew resources, or open access to yew trees by companies trying to develop alternative methods for producing taxol. Wyden also is concerned that Bristol-Myers Squibb could end up charging unconscionably high prices for taxol in light of the fact that most clinical research is being conducted at government expense. He compares the situation with the "high-price, high-profit commercial development of [the anti-AIDS drug zidovudine (AZT)] by Burroughs-Wellcome through inventions originated in federal laboratories." According to a report by Wyden's subcommittee, "A thorough review of the agreements, including confidential portions hitherto not revealed by the parties, demonstrates few specifics to keep the pricing lid on, let alone guarantee that consumers will not be gouged when and if drugs are manufactured and marketed." However, Saul A. Schepartz of NCI's Developmental Therapeutics Program says, "There are clauses built into the CRADA that take price into consideration. They do not specify costs per vial or anything like that. They do, however, recognize and take into consideration the contributions of the government that will be considered by Bristol-Myers Squibb in developing their price structure." Schepartz calls Bristol-Myers Squibb's efforts "a very difficult and a very expensive proposition. They are putting millions of dollars into procuring taxol for clinical trials, developing alternative sources for the drug so that we don't have to depend on bark any longer than absolutely necessary, and doing everything else needed to get the NDA approved." Bruce A. Chabner, director of NCI's Division of Cancer Treatment, points out that NCI could pull out of the CRADA and provide data to an alternative company if Bristol-Myers Squibb sets an unreasonable price on the drug. "Because taxol is not patented," he says, "other companies are able to develop this compound. Additionally, other companies are developing taxol analogs, some of which conceivably might be more effective or less toxic than taxol itself. We believe that these market forces also will limit the price of taxol." Indeed, taxol could one day see considerable competitive challenge from Taxotère, a patented taxol analog currently being developed by the French pharmaceutical firm Rhône-Poulenc Rorer. Taxotère differs from taxol by having a terf-butoxycarbonyl group instead of a benzoyl group on the C-13 side chain and a hydroxyl group instead of an acetoxyl group at C-10. These structural changes give Taxotère better water solubility and, hence, better bioavailability than taxol. Taxotère is prepared by a patented semisynthetic technique that begins with a taxol precursor isolated from yew needles. Phase I clinical trials of Taxotère began last year both in Europe and the U.S., and the drug is now entering phase II trials. In the phase I trials, 'Taxotère has re14
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vealed an activity that is very probably superior to that of taxol, in addition to [having] better bioavailability [and] solubility," says Pierre Potier, director of the Institut de Chimie des Substances Naturelles of the Centre National de la Recherche Scientifique (CNRS), in Gifsur-Yvette, France. Recently, Horwitz and coworkers found that Taxotère, like taxol, promotes microtubule assembly and inhibits cell replication [/. Natl. Cancer Inst., 83, 288 (1991)]. The patented process Rhône-Poulenc Rorer uses to produce Taxotère is based on the first successful partial synthesis of taxol, a technique developed by Jean-Noël Denis and Andrew E. Greene of Université Joseph Fourier, in Grenoble, France, and Daniel Guénard, Françoise Guéritte-Voegelein, Lydie Mangatal, and Potier at the Institut de Chimie des Substances Naturelles [/. Am. Chem. Soc, 110, 5917 (1988)]. The starting material for the partial synthesis, 10-deacetylbaccatin III, "can be readily extracted in high yield," they say, from the leaves of Taxus baccata, a European yew bush. Partial synthesis from readily available precursors is one of several strategies being investigated to provide adequate supplies of taxol. Greene, Potier, and coworkers believe the taxol shortage in the U.S. could be solved by applying their method. Because yew leaves are quickly regenerated, large amounts of 10-deacetylbaccatin HI can be obtained with negligible impact on the yew population, they say. "Taxol can be easily prepared through our patented process," says Potier. "Our group has solved the problem of the industrial production of taxol, and that of Taxotère." Greene adds, "We are today producing very large amounts of Taxotère." Bristol-Myers Squibb has licensed a similar partial synthesis developed subsequently by Holton and coworkers at Florida State University. The company is currently trying to scale up Holton's patented process for large-scale production of taxol. "In fairly short order—a year or two—we're going to need a lot of taxol, a lot more than can come from bark," says Holton. "What's the best way to get it? One alterna-
French researchers (left) Potier, Guéritte-Voegelein, and Guénard, and (above) Denis and Green developed partial synthesis of taxol, a process now used by Rhône-Poulenc Rorer to produce the analog Taxotère
tive is semisynthesis. And our own semisynthesis seems to work well, at least on the scale it's been run on so far." Holton also is working on a total synthesis of taxol, but that's not complete. "I wish I could tell you that we had the synthesis of taxol, but we don't have it all together yet. I'm hopeful that we will before too long, but you never know until it's over." The parts of the molecule that are the most challenging, says Holton, include the oxetane ring at C-4 and C-5, the hydroxyls at C-l and C-7, and the acetoxyl and ketone groups at C-9 and C-10. "We've addressed each of those problems separately," says Holton, "and have at least a rudimentary solution to each of them in different molecules. But we haven't gotten them all together in the same molecule yet." He says taxol synthesis represents "such unpredictable chemistry." Holton adds, "It is totally unknown. The ring systems are unexplored ground. The stereochemistry, the variety of substituents, the conformational peculiarities, the strange reactivity—my goodness, it's an incredible challenge." Many other research groups are working on synthesis of taxol, often under NCI grants. Workers in this area include chemistry professors William F. Berkowitz of Queens College of the City University of New York; Stephen F. Martin of the University of Texas, Austin; Leo A. Paquette of Ohio State University; Kenneth J. Shea of the University of California, Irvine; Charles S. Swindell of Bryn Mawr College; Paul A. Wender at Stanford University; and Jeffrey D. Winkler of the University of Pennsylvania. But this is only a partial list. Swindell has counted 30 or so research groups that have worked on organic synthesis of taxol and related compounds. "I think it's safe to say that taxol is one of the most important targets for synthesis chemists today," he says. Synthetic work on taxol also is frequently combined with efforts to identify taxol analogs. "Ultimately we hope to discover a really simple compound that expresses a lot of the activity of taxol and that you might
be able to put together more easily," says Swindell. "That's a goal of ours, in addition to the total synthesis of taxol." In a recent structure-activity study, says Swindell, "we looked at deletion analogs that result from removing various pieces of the C-13 side chain. It's been known for some time that that's a critical part of the structure for biological activity. We learned something about what's required in the side chain for activity to be expressed." The deletion analog study was carried out in collaboration with Horwitz and with Israel Ringel of Hadassah Medical School at Hebrew University, Jerusalem [/. Med. Chem., 34, 1176 (1991)]. Swindell adds, "You always hope to run across something that will turn out to be useful, but that's a bit of a shot in the dark. You go into work like this knowing that you can learn something about the structural features that are important for activity, whether or not the particular compound you're looking at will turn out to be a useful drug. That kind of information eventually can be parlayed into the design of a taxol mimic that hopefully will be more easily prepared, more readily available, and so on. But that's a long-term goal—I'm not suggesting it's just around the corner." Chemistry professor David G. I. Kingston and coworkers at Virginia Polytechnic Institute & State University are also doing structure-activity studies to determine which parts of the taxol molecule are essential for activity. "One of our key findings," says Kingston, "is that the oxetane ring of taxol is essential for its activity. This means that any active taxol mimic will probably have to incorporate an oxetane ring. We have also discovered a rearranged taxol molecule that retains at least the tubulin-assembly activity of taxol and may thus serve as a basis for future analog synthesis." Kingston's group also is interested in developing taxol prodrugs—compounds that are not themselves drugs but are converted into drugs in the body. "One of the major problems with taxol," says Kingston, "is the lack of water solubility. You have this complex emulsion formulation that is very difficult to administer. In phase I trials, they gave this in a fairly short period to patients, and at least one went into anaphylactic shock from reaction to the vehicle and died. They've gotten around this now by premedicating the patients and giving the drug over a long period of time. This is still not an ideal way to go, so a soluble prodrug analog would be an advance." So far, Taxotère seems to be the most successful taxol analog. Guéritte-Voegelein and coworkers at the Institut de Chimie des Substances Naturelles and at RhônePoulenc Santé, in Vitry-sur-Seine, France, have synthesized and tested about 40 taxol-like compounds for their ability to inhibit microtubule disassembly and found Taxotère to be one of the most potent [/. Med. Oiem., 34, 992 (1991)]. Another strategy being investigated to increase the availability of taxol is direct extraction of the compound itself from Taxus needles—a renewable resource because harvesting needles does not kill the tree. According to David R. Carver, chief executive of NaPro, in Boulder, Colo., T. brevifolia leaf "has between September 2, 1991 C&EN
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News Focus 20 and 70 ppm taxol in it, and the bark has anywhere from 70 to 400 ppm taxol. But the amount of leaf that's on the tree is at least twice, and perhaps three or four times, the poundage of bark. Say you have 50 ppm in the leaves and 200 in the bark. Since you have more poundage of leaf, you get just about the same amount of taxol out of the leaves as you do from the bark." The current practice by NCI, Bristol-Myers Squibb, and Hauser of extracting only the bark means "we're throwing away at least half the taxol that's available out of the forest," says Carver. Recently his company developed a new process for isolating taxol and taxol precursors from Taxus needles, and a patent has been applied for. "It's a very efficient process to get reasonably pure taxol and precursors from needles very quickly," says Carver. "We're scaling it up to produce large quantities of taxol from the leaves." At the Forest Service's Forest Products Laboratory, in Madison, Wis., researchers are also studying extraction of taxol from the heartwood of Pacific yew. Taxol concentration in the heartwood, like that in the leaves, appears to be lower than in the bark, but there is much more heartwood than bark. Pacific yew heartwood contains a minimum of 10 times and as much as 100 times more taxol than is currently obtained from the bark, according to Forest Products Laboratory chemical engineer Raj Atalla. Still another possibility is obtaining taxol from Taxus plants grown for ornamental use instead of in the wild. "Taxus plants are raised by nurseries for six to 12 years before they are sold," says botanist Edward M. Croom Jr. of the Research Institute of Pharmaceutical Sciences at the University of Mississippi. "The needles are trimmed every year, and right now those trimmings just fall to the ground and rot." Collaborative studies by Croom and University of Mississippi plant chemist Hala N. ElSohly have shown ornamental cultivars to contain taxol in the needles at levels equal to or greater than levels in T. brevifolia bark.
A collaborative project to produce taxol from ornamental plants is currently being planned by USDA; the University of Mississippi; Ohio State University; and Zelenka Nursery, in Grand Haven, Mich. Zelenka is coordinating the collection of clippings from nurseries throughout the U.S. "Yew clippings from ornamental nurseries offer the advantage of an immediate taxol supply from the millions of plants already in cultivation," says Croom. The project agreement calls for collection of needles and twigs from Taxus X media 'Hicksii', an ornamental yew shrub grown on plantations at large landscape nurseries. Project participants are currently planning the first commercial-scale collection and handling of Hicksii material and its delivery to NCI for extraction and purification of taxol. They estimate that the project could yield about 40,000 lb dry weight of Hicksii material—about 2.5 kg of taxol, after processing and handling losses. According to James C. Overbay, deputy chief of the National Forest System at USDA, the effort to obtain taxol from cultivars holds great promise. "However," he says, "we must keep in mind that this is a new type of research, and results from this work will help us understand the potential of this alternative source. In the meantime, traditional plant sources must be used to meet immediate research needs." An agreement signed last month between BristolMyers Squibb and Weyerhauser Co. also is emphasizing a domestic cultivation alternative to producing taxol. The agreement calls for the two companies to cooperate on production of taxol from genetically selected cultivars. Weyerhauser is currently growing more than 500,000 yew plants as starter materials for future production populations. Also under active investigation is the concept of producing taxol in cultures of cells grown in bioreactors. "Tissue culture can be a viable approach," says USDA plant physiologist Donna Gibson. "It means selecting a
Researchers studying synthesis of taxol and development of taxol analogs include (from left) Holton, Kingston, Faquette, Swindell, and Wender 16
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tern that doesn't violate the claims cell line that can overproduce taxol of that patent," says Howard. to begin with and then optimizing However, Walter E. Goldstein, it to a point where it's cost effec vice president of research and de tive. The challenge is getting the velopment at ESCAgenetics, re tissue into cell culture and then sponds, "The process we're using figuring out how to stimulate it to has been developed on our own produce taxol." and is separate and unique from Gibson and USDA coworkers Al the USDA patent. ESCAgenetics is ice Christen and John Bland devel not now infringing, and does not oped such a technique, and a U.S. intend to infringe, any valid claims patent for it was issued on May 23 of the USDA patent. We want to of this year. "It's a process for pro make an important contribution in ducing taxol and taxol-like com seeing that taxol supplies meet pounds in tissue culture," says Gib clinical needs." son. "The claims are fairly broad." Also being considered is tissueUSDA has signed a CRADA culture production of taxol precur with Phyton Catalytic Inc., Ithaca, sors as starting material for partial N.Y., to optimize the cell-culture synthesis of taxol. "I would very process. The CRADA gives the much like to see the tissue-culture company an exclusive license to Schepartz: a lot of phone calls from people try to culture baccatin III, produce taxol and like compounds people who are anxious to get taxol for various reasons," says Holton. in tissue culture. Phyton Catalytic "I'd like to see our semisynthesis president Rustin R. Howard says, used to make taxol. There might be "We expect commercial production some real advantages to that." of taxol from tissue culture in as soon as two years, and almost assuredly in five years." With so much research being done on different ways to produce taxol, there is considerable speculation about In June, a company called ESCAgenetics, in San Car what the best approach will be. In the short term—the los, Calif., also announced successful production of tax next one or two years—it seems clear that taxol from Γ. ol through plant cell culture, a development that brevifolia bark is the only viable way to go. The next best caused the company's stock to go up considerably in prospect is probably extraction from needles of cultivat value. "We successfully expressed taxol in tissue culture ed Taxus plants. less than nine months after initiating our taxol program and expect to scale up to commercial production within Carver believes that taxol production "will probably the next two years," says ESCAgenetics president and move to cultivars within about three years. It's a lot eas chief executive Raymond J. Moshy. ier just to grow bushes and shrubs that have high con tent of taxol and just trim them every year to get your Some charge that ESCAgenetics' tissue-culture process biomass. I think that's probably going to be the lowest may infringe on USDA's patent and hence Phyton Catacost taxol." lytics' exclusive license. "It's very difficult to think that NCI's Schepartz agrees that "the most likely bet for ESCAgenetics will produce taxol in a tissue-culture systhe first area of relief [from bark extraction] is use of needles direct ly." However, he also emphasizes the possibility of increasing taxol yields by using partial synthesis, such as the technique used by Rhône-Poulenc Rorer to produce Taxotère. "In many of the samples we've looked at," says Schepartz, "you have taxol and baccatin III there in equal amounts. So if Holton's semisynthesis process could be scaled up to a good efficient conversion, that could double your yield." Total synthesis is more problematical. "Total synthesis of taxol will ( be achieved in due course," says Paquette, "but the challenge of making it in a practical way is quite a different thing. I'm told by people at Bristol-Myers Squibb that a good 25-step total synthesis is something September 2, 1991 C&EN
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they would entertain with regard to producing taxol. We'd like to have a 20-step synthesis going for us in the end, but I don't think that's going to be feasible. Twentyfive is more realistic, and that's at the borderline. But it's much too early to tell. Things get refined and improved as you go along." Holton believes that a total synthesis would be of great scientific value. However, he says, "I don't think it will make much impact on the supply of taxol. [Taxol] is a very complicated molecule, and there are many synthetic challenges in it. Any total synthesis is going to be multistep, no matter how we pare it down and no matter how much we refine it. To think about total synthesis as an alternative for the supply of taxol on a commercial basis in the next five to seven years is probably not realistic." By that time, says Holton, "I expect that some taxol mimic, taxol surrogate, or second-round drug candidate will have been developed and may supplant taxol altogether. Such a drug may be totally synthetic, and I suspect that's where total synthesis may play its biggest role." Prospects for cell culture are as yet uncertain, but it could prove to be a viable alternative. "Cell culture has to be looked at as yet another means of generating taxol or like compounds, even as precursors for a semisynthetic route," says Gibson. NCI officials hope that within about two to three years, sufficient taxol will be available from one or another of these sources to provide some relief from de18
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pendence on Pacific yew bark. However, they believe that it will likely be four to five years before the need for bark is completely eliminated. Certainly, demand for taxol treatment is growing. "There are a lot of phone calls from people who are anxious to get it," says Schepartz. "Whether it's suitable for them or not is something that our clinical colleagues have to judge, and also that their physicians have to judge. Normally if I get calls from patients or family members I refer them to the clinical people." NCI's treatment referral center will discuss therapeutic options for specific cancer cases, including clinical trials that might be appropriate for a given patient. The telephone number, for physicians only, is (301) 4965725. If a patient appears to be suitable for one of the existing clinical protocols on taxol, NCI personnel will refer the patient to the particular institution where that's being carried out. In addition, says Schepartz, "Later on this year there will be some additional protocols established that will provide the drug on a compassionate basis to a larger number of patients who might benefit from it, but who might not be suitable for treatment under the existing protocols." But the problem of increasing the supply of taxol still looms large today. Organic chemist Paul Wender says he was surprised recently to receive a personal phone call from NCI director Samuel Broder "explaining the nature of the problem and telling us how desperate they are for this particular compound." This is but one indication of how earnestly Broder and other NCI officials are pursuing an answer to the taxol dilemma. "For the short term we will be living with inadequate supplies of this drug," Broder admits. "But in the long term the problem is going to be solved." D
