C&EN: BOOKS - A BLOCKBUSTER DRUG THAT ALMOST WASN'T

REVIEWED BY DAVID G. I. KINGSTON

Although taxol does not have quite the same potential as Viagra as a source of one-liners for late-night TV shows, it shares with the latter the distinction of being one of the few drugs instantly recognizable by name by a large proportion of the American public. In addition to its public renown--and partly because of it--Taxol has also helped to shape public perception of the importance of conserving biodiversity. Yet its development pitted preservationists against cancer patients and involved the U.S. government, represented by the National Cancer Institute (NCI), in a controversial partnership with the pharmaceutical company Bristol-Myers Squibb (BMS).

	THE STORY OF TAXOL: NATURE AND POLITICS IN THE PURSUIT OF AN ANTICANCER DRUG, by Jordan Goodman and Vivien Walsh, Cambridge University Press, 2001, 282 pages, $27.95 (ISBN 0-521-56123-X)

Jordan Goodman and Vivien Walsh provide a critical history of these developments in their well-researched book, "The Story of Taxol: Nature and Politics in the Pursuit of an Anticancer Drug." The authors, who are in the departments of history and of technology management, respectively, at the University of Manchester Institute of Science & Technology in England, take up the story in the early days of NCI when cancer chemotherapy was just becoming respectable. They trace it through the discovery of the chemical compound now known generically as paclitaxel by Monroe E. Wall and Mansukh C. Wani to its development at NCI and its eventual transfer to BMS, which markets it as Taxol. They end when the connection between the compound and the Pacific yew tree, Taxus brevifolia, was cut by the BMS decision to obtain its supply by semisynthesis from 10-deacetylbaccatin III.

Of course, the Taxol story does not end there, as evidenced by recent news stories on the ongoing saga of the efforts to market the generic drug (C&EN, Nov. 6, 2000, page 20). Goodman and Walsh's account is based on a thorough review of published and unpublished sources and also includes information from interviews with many of the major players.

The Taxol story is a complex one that is important in several respects. Taxol was the first plant-derived anticancer drug to come out of the exemplary natural products program at NCI. Sadly, this program was all but discontinued in 1981, although it was revived again in modified form in the late 1980s. Despite this discontinuity, several additional natural products are now in preclinical development or in clinical trials, and two natural product derivatives (Irinotecan and Topotecan, both derived from camptothecin) are in clinical use. The success of Taxol and to a lesser extent of the camptothecin-derived drugs serves in large measure to justify the program and to argue for its continuance in a time of increasing competition for funds from combinatorial chemistry and other approaches to drug discovery.

A second major importance of Taxol is that it really gave a tangible meaning to the concept of biodiversity, since for many years it was only available from T. brevifolia, a crucial component of the old-growth forests in the Pacific Northwest. The authors do an excellent job of tracing the linkage between Taxol and this tree and of describing the increasing efforts to collect T. brevifolia bark for preclinical studies and eventual clinical trials.

The supply of Taxol in the late 1980s was the major limiting factor in its clinical development. That supply was limited primarily for budgetary reasons; I do not agree with the authors that this was due to bureaucratic ineptitude, at least not by the personnel in NCI's natural products branch. It is true, though, that the senior management at NCI was not willing to commit the major resources necessary to open clinical trials of the agent in a big way. Sadly, one of the clinical trials that was put on hold by a lack of drug was a breast cancer trial. Breast cancer patients, we now know, are among those who can most benefit from the drug, so this delay both denied the drug to many women who could have benefited from it and reduced its apparent value to potential developers.

The connection between Taxol and T. brevifolia bark was not, in fact, an essential one, since the compound does occur in other parts of the tree as well as in other Taxus species. T. brevifolia bark was originally selected as the source because early experiments with alternative sources showed it to be the plant part with the highest percentage of the compound. It then got "locked in" as the source because of Food & Drug Administration regulations. The authors question the wisdom of this connection, and with hindsight it might have been better had the needles or another more plentiful plant part been selected, but the choice of bark was a reasonable one at the time it was made.

This choice did, however, put severe pressure on the tree, which gave rise to tensions between conservationists anxious to preserve the old-growth forests and the endangered northern spotted owl that lives there and cancer patients anxious to get the drug. The tension made great copy for news reports, giving rise to quotations such as, "Be damned the spotted owl, the rain forest, and the ecosystem, it is my wife's life we are talking about."

The demand for Taxol from the Pacific rain forest stimulated interest in preserving biodiversity and in deriving value from it, and this was part of a mix of forces that led to the Convention on Biological Diversity in 1992 and to the formation of several international cooperative biodiversity groups in 1993. It also led to "Taxus rustling," as well as to a cottage industry of legal bark collecting in Oregon and Washington, with people hoping that a new industry could be developed to replace jobs lost through the decline of logging. The authors do a thorough job of tracing the rise of the independent collectors; the takeover of the business by Hauser Chemical Research, acting as the sole-source supplier to BMS; and Hauser's own decline when BMS moved to a semisynthetic approach to Taxol production. In the end, inevitably but sadly, T. brevifolia was not to be the basis for an economic boom in the Northwest.

A whole chapter in the book is devoted to the Cooperative Research & Development Agreement (CRADA) by which BMS obtained the rights from NCI to develop Taxol. The deal was controversial, in part because various people once employed by NCI had moved to BMS, but also because BMS received the rights to develop Taxol without compensating NCI in any way for all the work it had done to bring development to the point of commercial interest. One particular clause, "The United States Government will receive a reasonable share of income once the drug is marketed for general use," which had been a part of the draft CRADA, was inexplicably removed from the final version.

A part of the explanation for this "giveaway" is that in 1989 when it occurred, the gift appeared to be much less valuable than it eventually turned out to be. As noted above, Taxol's activity in breast cancer was not known in 1989; at that time it was only known to be active against ovarian cancer. Since ovarian cancer is much less common than breast cancer, BMS estimated the market potential of the drug to be in the range of $200 million to $300 million per year, and there was serious doubt within the company as to the wisdom of bidding on the CRADA.

In the end, with strong encouragement from NCI, BMS did make a bid, and it was the only major U.S. pharmaceutical company to do so. It was the eventual winner over the French company Rhône-Poulenc, which had a competing drug in Taxotere, discovered by Pierre Potier. So selection of BMS made sense from a competitive point of view.

The difficulty of finding a developer for Taxol, even though it was known to have clinical activity, points up the critical importance of NCI in the discovery and development of new anticancer drugs. Clearly, the compound would never have been developed without NCI's involvement. BMS's involvement in commercializing the drug was also crucial. The company did an impressive job of developing the supply to the point where there was no longer any shortage, even in the face of large demands for breast cancer treatment.

The authors also touch on the issue of the trademarking of the name Taxol but profess to be at a loss as to how BMS was able to trademark such a well-known name. In fact, the name Taxol had been trademarked in the 1930s by a French company for a laxative product, and BMS was able to purchase the trademark. It is still not clear, however, how BMS managed to persuade the Patent & Trademark Office that the laxative trademark should apply to an anticancer drug, particularly as the name had been in common use for over 20 years without any attempts to enforce the trademark.

The final importance of Taxol is in its use as an anticancer drug. It rapidly acquired the status of a "blockbuster" drug, with sales of more than $1 billion per year, in part because of the high drug cost for a course of treatment. Nevertheless, it is an effective drug for ovarian cancer, breast cancer, non-small-cell lung cancer, and Kaposi's sarcoma. My oncologist son-in-law tells me that oncologists refer to the period before 1994 as the "pre-Taxol" era when referring to breast cancer treatment, powerful testimony to the impact the drug has had on treatment of this disease.

An observation deserves to be made on the lengthy development time of Taxol as an anticancer drug. Although the compound's structure was not published until 1971, both its structure and activity were known by Wall, Wani, and others at NCI as early as 1969, 20 years before its clinical activity was announced by William P. McGuire and coworkers in 1989.

Why was there such a long delay? The answers relate primarily to problems of solubility (Taxol has a solubility in water, according to one researcher, like that of brick dust) and supply. A more subtle answer, and one brought out in this book, was the fixation within NCI on assays for antileukemic activity, where the compound did not stand out.

It was not until new assays for activity against solid tumors were developed in the mid-1970s that the compound's true worth could be seen. Thus development of Taxol was initially approved based on its activity against one type of melanoma in mice, thanks to the championship of Matthew Suffness and Wall, although it was nearly dropped when the compound's activity in this assay was found to be limited to one route of administration. It was saved by the introduction of new xenograft assays, in which human tumors are grown in athymic mice. Here the compound showed remarkably good activity, especially against one model for breast cancer.

It was nearly dropped again when early clinical trials revealed severe hypersensitivity reactions in some patients. It was saved this time largely by Peter H. Wiernik at the Albert Einstein Cancer Center in New York City, who believed in it in part because of his colleague Susan Horwitz' discovery in 1979 of its unique mechanism of action.

"The Story of Taxol" will appeal to many people, from oncologists interested in the history of one of their best weapons to conservationists interested in how best to use and yet protect the world's biodiversity. There are a few factual errors, but none are significant. It is, however, unfortunate that Wani's name was omitted from the story of the structure elucidation of Taxol, since he was a prime contributor to this work, and that more credit was not given to Suffness, without whose vision and encouragement we would not have the drug today.

Nevertheless, this is a very readable and reliable account of the development of Taxol through 1992. The story reminds us of the bounty nature provides us with, but also of the perseverance and, yes, good luck needed to take advantage of that bounty.

David G. I. Kingston (dkingston@vt.edu) is a professor of chemistry at Virginia Polytechnic Institute & State University, where he studies the chemistry of natural products. He has worked on the chemistry of paclitaxel/Taxol since the early 1980s.