The Story of Taxol: Nature and Politics in the Pursuit of An Anti-Cancer Drug (review)

At the beginning of the 20th century, the embryonic pharmaceutical industry depended almost entirely on extractive, synthetic, and analytical chemical techniques to reveal and purify the active principles of several plants, and to devise the industrial processes that were increasingly offering medicinal compounds such as aspirin. Biological processes, including the raising of anti-toxic sera and the preparation of glandular extracts, were slowly increasing in usage, coming to fruition in the discovery of insulin after the First World War.

After the Second World War, the nature of drug discovery changed a great deal, as increased understanding of drug-receptor interaction led to rational drug design increasingly becoming the accepted and successful way to pharmaceutical innovation. The deliberate and considered molecular manipulation of biologically active moieties gave rise to a raft of new remedies against an enormous range of diseases and disorders.

The anti-cancer drug Taxol, first marketed in the mid-1980s, includes elements of both these routes of discovery.This fascinating story starts in 1953, when the U.S. government initiated a search for anti-cancer drugs, a "war against cancer" later mirrored by Nixon's "war on drugs." A prime focus of the 1950s campaign was the examination of the medicinal properties of native plants. A number of organizations became involved, from government policy makers and the scientists and clinicians of the National Cancer Institute, to the plant collectors and botanists trekking through the National Forests of North America, collecting thousands of plants for chemical and pharmacological examination. From these huge endeavors, one species of the yew,Taxus showed particular promise. This was Taxus breviolata, the slow-growing Pacific yew, a little-known member of the family, although further tests on specimens from other species revealed considerable variation throughout the genus and raised the possibility that more than one species might provide an active anti-mitotic agent. Differences of attitude between chemists and taxonomists, the former insisting on a "pure" sample, the latter emphasizing the similarities between the different Taxus species, resulted in a convenient (for the chemists) operational focus on Taxus breviolata. The difficulties of obtaining the large quantities of bark, the stripping of which destroyed the tree, required for the next stage of chemical analysis and toxicological tests seemed not to have worried the cancer researchers, nor many of the plant gatherers. Neither did the fact that Taxus breviolata was not a cultivated species. In the early 1960s, their goal was an anti-cancer agent, and the ecological price, if any, was not considered. Until the mid-1970s, comprehensive examinations were made of the bark of Taxus breviolata, and the isolation of a laboratory-active chemical extract led to the discovery of an identified molecule, calledTaxol (curiously, also the name of a 1930s laxative), which then passed though a battery of laboratory tests and into preliminary clinical trials. But simultaneously, the climate of opinion about the natural world was changing. The environmental movement that had blossomed during the 1960s had strong views on the willful desecration of trees, even if the result was a possible cancer treatment. Several sins of omission came home to roost: the lack of forethought in focusing completely on Taxus breviolata to the exclusion of other, more abundant and more easily replenishedTaxus species; the want of any plans to re-stock the depleted plants; the way in which the lower yield of the yew's renewable pine needles had been ignored in preference to the higher yielding, but fatal stripping, of bark; and the half-hearted attempts that had been made to achieve chemical synthesis of the active compound.

Whilst difficulties with the collection of the raw ingredients and preparation of the drug were negotiated and resolved, several teams around the world were developing synthetic pathways, and toxicity tests...