Current Issues/Future Applications

In recent history, the controversial issues surrounding taxol and the Pacific yew mostly dealt with efforts to obtain sufficient quantities of the chemical compound to sustain experimental investigations. The problem was one of availability. As the clinical trials showed that taxol was a very potent anticancer agent, the demands for the drug grew greater and greater. It came to the point that there was just not enough taxol to go around. Taxol has a concentration in the bark of Taxus brevifolia of about 100mg/Kg of bark. The average 100 year old tree yields only about 3Kg of bark. As indicated, it takes about 100 years for the tree to reach the required dimensions for such a harvest, and the tree must be sacrificed in the process. One complete course of treatment requires 2g of taxol, which would be the equivalent of at least 6 trees. With the tremendous anticancer potential shown and clinical demand escalating, the largest debate concerned the harvesting of the bark. Between 1987 and 1988, about 60,000 pounds of bark were collected. The collection of the bark was difficult and could only be done for part of the year. Another problem was that about 18-24 months of work were required to take the bark to a form of the drug that could be administered. This lead to serious time constraints. In 1989 there was a second harvest that yielded another 60,000 pounds of bark. It was at this time that concerns were raised about the impact of all these collections on the survival of the tree. Environmentalists, fearing that the tree could become extinct, requested that it be put on the endangered species list. This request was subsequently denied, citing the fact that there were about 1.8 million yew trees in the forests of the western states. To add to the chaos, a black market for the bark was created due to its increasingly greater demands. To combat this problem, a $10,000 fine was enacted for anyone caught pouching the bark.

In the ensuing years, larger amounts of the bark were being harvested. 1991 and 1992 saw 1.6 million pounds being collected. It was clear that these exceedingly high rates of harvesting could not be maintained, even though the demands kept growing and growing. A new source of taxol would have to be devised. This is exactly what happened when it was shown that the needles of Taxus baccata, a related species of yew tree, could be used as a source for a compound called 10-deacetylbaccatin III, which has similar characteristics to taxol. Organic chemists demonstrated that one could transform this compound to taxol in the laboratory using a short synthetic sequence. Although specific strategies must be used to make the synthetic compound biologically active, the fact that the needles could be harvested without killing the plant represented a renewable source for taxol. Early in 1994, however, two total syntheses of taxol were reported by the Holten group from Florida State University and the Nicolaou group of the Scripps Research Institute. The two approaches are different, but both involve the complete synthesis of taxol in the laboratory without the use of any precursor obtained from the plant. With these two syntheses for taxol, studies to make them more efficiently and to make structural analogues of taxol are now in progress. These promising new revelations could lead to the production of a cheaper, more effective drug. In addition to these findings, Professor John S. Oliver at Brown University is currently conducting research to identify the binding site of taxol on the polymerized tubulin molecules. He is attempting to find the exact amino acid or amino acid sequence that taxol reacts with on the polymerized tubulin dimer. If this site is identified, then any molecule that activates this site will polymerize the microtubules of a cancerous cell in the same way that taxol does. This could possibly enable scientists to create a new, easily synthesized molecule that can activate those sites specifically. With exciting discoveries such as these, it's no wonder why the atmosphere for cancer researchers today is a very highly charged one.

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