The Anti-Cancer Drug Taxol: A Case for or Against Chemical Prospecting?

Vanessa Hill

Colorado State University

Fort Collins, Colorado 80523

Abstract

Chemical prospecting has developed recently as an argument for preserving 

biodiversity.а The idea is that in biodiversity lies unknown molecules and genes 

that have potential uses such as drugs for human diseases.а The development of the 

anti-cancer drug taxol from the Pacific Yew tree (Taxus brevifolia) in the United 

States is discussed as an example of the process of chemical prospecting. By 

examining the history and current status of taxol, positive and negative aspects of 

chemical prospecting are considered.

Introduction

Most people would agree that biodiversity is important and are concerned with its 

rapid rate of destruction. However, it appears that often it is difficult to justify 

exactly why biodiversity is so valuable.а Why not slash and burn the rainforest for 

agricultural purposes? What is the value in the biodiversity found in a healthy 

rainforest ecosystem? One argument that strives to put a value on that diversity is 

based on the molecular and genetic potential it represents.а Specifically, as 

sources of future drugs and chemicals that have unlimited potential to further 

mankind.а In recent literature, Tom Eisner has given this line of reasoning the name 

"chemical prospecting" (1,2).

Chemical prospecting is a multi-step process that begins by screening organisms for 

molecules or genes for a particular function, often potential sources of drugs to 

treat diseases.а Once a natural product has been identified as useful, at least some 

of the source organism is collected for further study.а This natural product then 

has value to pharmaceutical companies because it can be developed into a marketable 

drug either made directly from the source organism, or by synthetic processes.а This 

monetary windfall from the drugs then leads to money that will be reinvested into 

conservation of the original benefactor, biodiversity (1).

While rainforests are often the focus of biodiversity discussions, a superb 

illustration of the process of chemical prospecting is on-going in the United 

States.а The story involves a tree of little appreciation and the powerful anti-

cancer agent found in its bark.а The tree is the Pacific Yew (Taxus brevifolia) and 

the drug is a diterpenoid named taxol.а The discovery and development of taxol for 

the treatment of cancer warrants an in depth look, not only for illustrating how 

chemical prospecting works, but also how it doesn't work.

Discovery of Taxol

Taxol was discovered through a prospecting venture begun in the 1960s by the 

National Cancer Institute (NCI) in cooperation with the US Department of 

Agriculture. These agencies began screening plant tissues in North America for anti-

tumor activity in the hope of discovering new treatments for cancer (3). In 1962, 

tissues from the Pacific yew tree were collected by USDA workers and sent in for 

analysis.а The initial screening showed extracts from the yew to have cytotoxicity 

activity against human cancer cells (3).а This success caught the attention of the 

NCI and the yew extracts were targeted for more intensive research at one of the 

NCI's research institutions.

A research team led by Dr. Wani at the Research Triangle Institute received the yew 

assignment and began to isolate the active compound.а This process was begun by 

water-chloroform fractionation of bark extracts directed by bioassay results (4).а 

The primary bioassay used to detect activity in the fractions was a test against 

leukemia cells (4).а Once the compound in the active fraction had been isolated, Dr. 

Wani's team began to determine the structure of the compound.а Mass spectrometry 

showed the molecular weight of the compound to be 853.а X-ray analysis was then used 

to determine the structure of the molecule.а However, this was not possible on the 

entire molecule, and it had to be cleaved by base catalyzed methanolysis into 

subunits that could be identified with x-rays (3,4).а The final structure was 

completed with alkaline oxidation with MnO2 to define the structure of the molecule 

named Taxol (3) (Fig. 1). In 1971, Wani et al. published their results on taxol as 

the first molecule at that time with a taxane ring to have anti-cancer activity (4).

Despite this achievement, NCI then lowered the priority in continuing research on 

taxol (3).а The compound was difficult to obtain because it is present in relatively 

low concentrations in the bark of the Yew tree, (.5 g for 12 kg of bark) and the 

anti- leukemic activity was not considered dramatic enough to warrant continued 

research (3). Taxol research then remained stalled until 1977.а Around this time it 

was realized that the leukemia bioassay used to asses taxol's effectiveness was 

relevant towards human leukemia, but was not a good test for activity against solid 

tumors.а Another bioassay that had also been used by Wani's group on melanoma cells 

(solid tumors) had much more dramatic positive results and this stimulated interest 

in taxol again and led to its development (3).

Development of Taxol: the supply problem

The research on taxol then proceeded on two fronts, one to determine how taxol 

worked and the other to determine its effectiveness in cancer patients.а By the late 

1970s, the mechanism of taxol was known to be enhancement of microtubule 

polymerization such that the dividing cells were stalled in the G-2 phase and do not 

depolymerize (5,7). Clinical trials then proceeded through the 1980s on various 

forms of cancer.а Specifically, taxol has proven to be effective against ovarian, 

breast, lung, head and neck, and esophageal cancers (7).а The use of taxol has been 

approved by the Food and Drug administration for use in treatment of two of these 

cancers, ovarian and breast (7).

 Due to the success in clinical trials, the NCI offered the right to develop the 

drug competitively to drug companies.а In 1991, the company Bristol-Meyers Squibb 

(BMS) won this right (3).а Since the source for taxol was the Pacific Yew tree, BMS 

and the NCI entered into an alliance with the US Forest Service and the Bureau of 

Land Management, the two agencies who had access and control of the yew tree supply 

on public lands (8).а The initial step in this process was to determine the supply 

of yew bark in the US.а Even though the yew tree ranges along the west coast of 

North America from British Columbia to California with inland populations in Idaho 

and Montana, relatively little was known about its abundance.а T. brevifolia had 

previously been considered unimportant economically and therefore no money had been 

invested by government agencies to record any information on the tree (8).

The obvious economic potential of a cancer treatment then stimulated research on the 

Pacific yew.а An Environmental Impact Statement prepared by the US Forest Service 

identified several roles of the yew in its environment.а Specifically, habitat for 

the spotted owl, winter food for large herbivores and microhabitat for invertebrates 

were identified (8).а It is not surprising that the yew tree is important to many 

different aspects of the environment, as most organisms are tightly intertwined 

within their respective ecosystems.

Harvest of the Pacific Yew may have proceeded unabated, despite its role in the 

forest ecosystem, if not for one problem.а The concentration of taxol in the bark of 

the tree is extremely low.а A 100 year old tree might yield 3kg of bark which 

provides enough taxol for one 300mg dose (6).а By 1991, harvest of bark was up to 

around 425,000kg, at 3kg a tree that is over 100,000 trees that year (8).а The 

public became justly concerned at such harvest since bark cannot be harvested 

without killing the tree.а This concern in part stimulated the passage of the 1992 

Yew Act which stated that there should be a "sustainable harvest" that provided for 

the long term viability of the yew tree but still provided enough taxol for Bristol-

Meyers Squibb (8).

 Such determinations are difficult to make, what BMS requires for its research may 

overlap significantly with what may be considered a "sustainable harvest".а 

Furthermore, it is interesting that the Environmental Impact Statement was not 

completed until 1993, a year after the Yew Act was passed.а Thisа casts doubt on how 

"sustainable harvest" was defined when the basic ecology of the tree had not yet 

been determined.а In addition, as the figures from 1991 harvest indicate, 

significant amounts of bark were being harvested without any knowledge as to how 

that might impact the environment.а The policy of taxol collection appeared to be 

driven immediately by demand and environmental concerns were an afterthought.а This 

clearly demonstrates one difficulty with natural products prospecting, in that the 

enthusiasm for a new treatment can preclude any consideration of the effects of 

collection. The very biodiversity that was defended to provide the drug initially 

was degraded.а For example, along with the yew trees may have gone an equally 

important invertebrate, that depended on the yew tree's habitat, with unknown 

medicinal properties in its own right. 

Solutions to the Supply Problem:а alternative sources of taxol

In defense of the prospectors developing taxol, it was readily apparent to them that 

long term use of taxol was going to require an alternate, probably synthetic, source 

of the drug.а Unfortunately, the complex structure of this molecule does not lend 

itself to simple or rapid synthesis.а Only recently (1994), has the total synthesis 

of taxol been reported (9).а This synthesis is summarized in Figure 2 to illustrate 

the complexity of this process.а Although this synthesis was a formidable 

achievement, reviews by other workers do not support this as a practical or 

economical way to dramatically increase the supply of taxol (3,6).

One way to circumvent this problem is with a semi-synthesis starting with a more 

readily available precursor.а This is currently being investigated with the 

precursors baccatin III and 10-deacetylbaccatin III which are isolated from the 

needles.а These compounds can be found in several Taxus spp. which alleviates some 

of the pressure on T. brevifolia (3,10).а However,а taxanes isolated from the 

needles degrade more rapidly than taxol from the bark, which can be stored for 

longer periods of time due to its increased stability (11).

Yet another possible solution to the supply problem is developing plant cell 

cultures to produce taxol.а Progress in this area has not been rapid because taxol 

is difficult to generate in this way.а A primary difficulty is the relatively slow 

growth of plant cells, but research continues to overcome this (12).а Apparently, 

this line of research may be more advanced than is widely known because it is 

believed that corporate developments may be withheld until success is achieved (10).

One unique potential supply of taxol has arisen through work of Gary Strobel and his 

lab (13,14,15).а They have identified an endophytic fungi of the yew tree, Taxomyces 

andreanae, that produces taxol when grown in culture.а Similar to the other 

synthetic methods, the production by the fungi at this time does not represent a 

rapid or significantly large supply of taxol.а As with the others, time and 

continued research may correct this.

Implied, if not directly stated, in the reasoning for chemical prospecting is the 

idea that diverse organisms are needed only for the initial suggestion for a drug.а 

After discovery, mass production of the drug can be accomplished artificially to 

reduce the burden on the environment (11).а The difficulty in doing so with taxol 

demonstrates the flaw in this assumption.а Furthermore, there is no reason to expect 

that taxol is the exception and not the rule.а Cragg and Snader from NCI summarized 

the taxol supply problem in 1991 (11), and stated that it should not be assumed that 

large scale production of natural products is possible since these molecules tend to 

be complex and challenging to synthesize in part due to a high degree of chirality.а 

In addition, each new synthetic version of a drug must undergo its own approval from 

the FDA which can take 1-2 years.а Such delays mean that in the meanwhile, the 

natural source of a drug must continue to be tapped.а They also note in 30 years no 

synthetic source has been developed for the anti- cancer drugs vinblastine and 

vincristine which are still harvested from their original plant source (11).а Thus 

far, taxol in not much different, it has been 25 years since the discovery of taxol 

and no large scale, synthetic method has been developed.

Considerations of "Chemical Prospecting"

So then the saga of taxol remains stymied for the moment in the supply issue.а 

Research on the drug, for its function, effectiveness and synthesis continues and 

the promising results against solid tumor cells appears to ensure continued interest 

in developing the drug.а Not having a large supply for the general public certainly 

does not mean chemical prospecting has failed, it is merely stalled. Therefore, does 

the development of taxol indicate a success such that future prospecting should go 

on? Or does it show potential pitfalls in the argument for preserving biodiversity 

for future prospecting?

Potential trouble spots have already been mentioned in the review of taxol.а For 

example, the immediate exploitation of the source organism before any impact of 

collection has been assessed.а Also, that it cannot be assumed that all natural 

products lend themselves efficiently to synthetic techniques.а While these and other 

practical matters are of concern, scrutiny of chemical prospecting on a 

philosophical level raises other issues.

A recurring theme in Eisner's papers (1,2) is the value in biodiversity because of 

these potential cures and treatments for human disease.а Eisner does acknowledge 

that species have worth other than chemical potential(2), but he does not expand on 

these. This implies that other measures of value are not sufficient to defend 

biodiversity.а Therefore, the assumption within this argument is that intrinsically, 

biodiversity has no value.а This is demonstrated with taxol explicitly.а The yew 

tree was considered so unimportant that it was ignored in surveys done by the US 

Forest Service and the Bureau of Land Management over the last century.а When taxol 

became important the agencies had no idea even how many trees there were.а 

Furthermore, when timber was clearcut, the policy was to burn yew trees along with 

other scraps and waste (8). This changed when taxol was discovered and the yew tree 

now had value, economically and medically.а Logging practices shifted from wasting 

yews as trash to developing management techniques for "sustainable yield".а So it 

seems chemical prospecting saved the yew tree and some of the biodiversity 

associated with it.а However, it may also be said that chemical prospecting furthers 

the attitude that the destruction of a species is wrong only if it has some economic 

value or potential.а So biodiversity is still left with no inherent value, and 

therefore is still difficult to defend.

Somewhere along the way Western culture placed humans well above all other animals 

and consequently above all other organisms.а This disregard for 'lower' organisms 

makes it difficult to use and not abuse biodiversity. A critical response to 

chemical prospecting by Downes and Wold noted this tendency of "industrial 

societies" to destroy biodiversity through its use, unlike indigenous peoples who 

use biodiversity within its boundaries (17).а Steven J. Gould expresses this 

phenomenon as a "picket fence around Homo sapiens" that rests on the beliefs that 

"humans have not only transcended the ordinary forces of nature, but all that came 

before was...a preparation for out eventual appearance" (16).а It is a philosophy 

deeply entrenched in policy, especially in conservation issues.а It is this 

elevation that enables people to assume they have the intelligence and capability to 

'manage' biodiversity.а The environmental impact statement drawn up for the Pacific 

Yew tree carried an implicit assumption that there was one set of the right 

guidelines that would enable a "sustainable yield" such that all parties would be 

satisfied and the forest would be in ecological balance.

 It may be argued that the goal of sustainable yield is not to be perfect, but to do 

the least damage.а If so, then the idea of chemical prospecting as an argument for 

preservation is flawed.а If it is not possible to avoid altering an ecosystem to 

collect a newly discovered drug then how is the biodiversity of the system to be 

maintained?а It would seem the purpose of chemical prospecting is to preserve 

biodiversity until something useful is found.а The further loss of biodiversity in 

the harvest of the useful organism is secondary.

 Another flaw with using prospecting to defend biodiversity is that it is short 

sighted in its vision.а The main loss of biodiversity is through loss of habitat for 

an expanding human population and its perceived needs.а Eisner even recognizes this 

when he writes "human expansionist demands can be expected to wreak environmental 

deterioration and biotic destruction well into the next century"(2). If this 

expansion is due in part to improved life expectancy and infant survival due to 

modern medicine, prospecting potentially feeds the destruction of biodiversity.а For 

example, ovarian cancer, against which taxol is particularily effective, is the 

fourth highest cause of death in American women (7).а Eliminating this could 

contribute further to an ever-expanding human population.а Stepping back a bit, 

suppose large areas of northwestern forests were set aside as reserves of 

biodiversity due to the example set by taxol.а The new drugs developed from these 

reserves might lower mortality rates and thus the population would increase. Where 

is this increased population going to live?а With what resources are they going to 

sustain themselves? From what forests are they going to get wood to build houses?а 

The problem with maintaining biodiversity is largely habitat destruction from 

expanding human populations. Developing drugs to further this expansion means in the 

distant future biodiversity will be harder to defend due to prospecting, not easier.

Despite this, preservation of biodiversity is not hopeless. Clearly, for the short 

term, the potential of biodiversity for life-saving drugs is appealing and may stall 

current destruction of areas like the Amazon rainforest.а Legislation may also 

provide temporary fixes, but later generations can always rewrite laws when they 

really need all the timber in previously designated wilderness areas. Chemical 

prospecting needs to be considered for the long term and in a global context.а Plans 

need to be made for harvesting source organisms to maintain biodiversity and for the 

ultimate implications of those products on global population growth.а Furthermore, 

there must be a realization that biodiversity has intrinsic value that is not 

measured solely in immediate human benefits.а Only this kind of fundamental shift in 

how biodiversity is valued will provide lasting protection far into the future. 

REFERENCES

1. Eisner, T. and E.A. Beiring. 1994. Biotic exploration fund- protecting 

biodiversity through chemical prospecting.а BioScience 44(2):95-98.

2. Eisner, T. 1991. Chemical prospecting: A proposal for action. pgs. 196-202 in 

F.H. Bormann and S.R. Kellert eds. Ecology, Economics, Ethics-the broken circle. 

Yale University Press, New Haven.

3. Wall, M.E. and M.C. Wani. 1995. Paclitaxel: from discovery to clinic.а pgs 18-30 

in G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane Anticancer Agents: 

basic science and current status. ACS Symposium Series 583, Washington D.C.

4. Wani, M.C., H.L. Taylor, M.E. Wall, P. Coggon and A.T. McPhail. 1971. Plant 

antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and 

antitumor agent from Taxus brevifolia. J. of Am. Chem. Soc. 93(9): 2325-2327.

5. Schiff, P.B.. J. Fant and S.B. Horwitz. 1979. Promotion of microtubule assembly 

in virto by taxol. Nature 277:665-667.

6. Horwitz, S.B. 1994. How to make taxol from scratch. Nature 367: 593-594.

7.Holmes, F.A., A.P. Kedelka, J.J. Kavanagh, M.H. Huber, J.A. Ajani and V. Vlaero. 

1995. Current status of clinical trials with paclitaxel and docetaxel. pgs 31-57 in 

G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane Anticancer Agents: basic 

science and current status. ACS Symposium Series 583, Washington D.C.

8. Campbell, S.J. and S.A. Whitney. 1995. The pacific yew environmental impact 

statement. pgs. 58-71 in G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane 

Anticancer Agents: basic science and current status. ACS Symposium Series 583, 

Washington D.C.

9. Nicolaou, K.C., Z. Yang, J.J. Liu, H. Ueno, P.G. Nantermet, R.K.Guy, C.F. 

Claiborne, J. Renaud, E.A. Couladouros, K. Paulvannan and E.J. Sorensen. 1994. Total 

synthesis of taxol. Nature 367:630-634.

10. Suffness, M. 1995. Overview of paclitaxel research: progress on many fronts. pgs 

1-17 in G.I. Georg, T.T. Chen, I. Ojima and D.M. Vyas eds., Taxane Anticancer 

Agents: basic science and current status. ACS Symposium Series 583, Washington D.C.

11. Cragg, G.M. and K.M. Snader. 1991. Taxol: the supply issue. Cancer Cells 3(6): 

233-235. 

а12. Ketchum, R.E.B., D.M. Gibson and L. Greenspan Gallo. 1995. Media optimization 

for maximum biomass production in cell cultures of pacific yew. Plant Cell, Tissue 

and Organ Culture 42: 185-193. 

13. Strobel, G.A., A. Stierle and F. van Kuijk. 1992. Factors influencing the in 

vitro production of radiolabeled taxol by Pacific yew, Taxus brevifolia. Plant Sci. 

84: 65-74.

14. Stierle, A., G. Strobel and D. Stierle. 1993. Taxol and taxane production by 

Taxomyces andreanae, and endophytic fungus of pacific yew. Science 260: 214-216.

15. Stierle, A., G. Strobel and D. Stierle. 1995. The search for a taxol-producing 

microorgansim among the endophytic fungi of the pacific yew, Taxus brevifolia. J. of 

Natural Prod. 58(9): 1315- 1324. 

16. Gould, S.J. 1980. In the midst of life. pgs. 134-144 in The Panda's Thumb: more 

reflections on natural history. W.W. Norton and Company, New York.

17. Downes, D.R. and C. Wold. 1994. Biodiversity prospecting: rules of the game. 

BioScience 44(6): 381-383.аааааааааааааааааааааааааааааааааааааааа