25 No. 4
July - August 2003
and Taxol - The
Story Behind the Science
Nicholas H. Oberlies, Sharla Flora, and Anna L. Weaver
April 2003, many researchers and friends gathered on the campus
of Research Triangle Institute (RTI) International in Research
Triangle Park, NC, for a ceremony designating the site as
an American Chemical Society (ACS) National Hisoric Chemical
Landmark. This honor recognizes the work of RTI’s Natural
Products Laboratory and its scientists Dr. Mansukh Wani, the
late Dr. Monroe Wall, and their colleagues, whose dedication
and innovation led to the discovery of the unique cancer-fighting
compounds Taxol® and camptothecin™.1
Present to laud these accomplishments were representatives
of ACS and eminent researchers in the fields of natural products
chemistry, cancer pharmacology, clinical oncology, and others.
with many groundbreaking scientific developments, the stories
behind the discoveries of Taxol and camptothecin are compelling.
They provide more than good scientific narrative; these compounds
have far-reaching impact both on individuals afflicted with
cancer and on the field of natural products chemistry.
Wani (left) and Dr. Oberlies (article author) stand with
a plaque designating the Research Triangle Institute a
National Historic Chemical Landmark.
and Interest: Beginning with Camptothecin
for the U.S. Department of Agriculture (USDA), Dr. Wall spent
much of the 1950s researching a large collection of plants,
searching for phytosteroids that could serve as cortisone
precursors. Fortunately, Dr. Wall had the foresight to save
all the extracts from his studies. Later that decade, the
National Cancer Institute (NCI) launched a program to screen
plants for anticancer activity. Of the 1000 samples Dr. Wall
initially sent to NCI for testing, one demonstrated particularly
promising anticancer activity: Camptotheca acuminata, a plant
native only to China and Tibet, where it is known as xi shu
modeller view of Taxol
S. Wayne Mascarella, Ph.D., of RTI
its focus on agriculture, the USDA did not share Dr. Wall’s
interest in studying cancer-fighting plants. Therefore, with
the promise of funding from NCI, Dr. Wall took his passion
to the newly formed RTI. In 1962, Dr. Wall was joined by Dr.
Wani—and a scientific partnership that would last over
four decades was born.
Natural Products Laboratory acquired a large sample of C.
acuminata and began work to isolate and determine the structure
of the active agent. One of the more formidable challenges
was to make a crystal suitable for X-ray analysis. In this
area, among others, Dr. Wani demonstrated unusual skill. The
research team persisted, and success came in 1966, when Dr.
Wall, Dr. Wani, and colleagues published the isolation and
structure elucidation of camptothecin.
and Taxol: Timeline
of active compound from amptotheca acuminata; determination
of structure of camptothecin
of active compound from Taxus brevifolia; determintion
of structure of Taxol
of mechanism of action of Taxol
of mechanism of action of camptothecin
problem of Taxol abated via semisynthesis of Taxol
approval of Taxol for use in ovarian cancer, then subsequently
breast and lung cancers and Kaposi’s sarcoma
approval of two analogs of camptothecin for treatment
of ovarian, lung, breast, and colon cancer
paper was their first publication on an anticancer compound
from a plant source. Interestingly, Dr. Wall presented results
at the annual meeting of IUPAC in Stockholm, Sweden, that
same year. The seminal nature of this initial publication
is rather remarkable, and it would lead eventually to camptothecin
analogs used today in the fight against cancer.
obstacle encountered by the research team involved the natural
form of camptothecin. Specifically, its poor water solubility
makes drug delivery extremely difficult. Clinical trials with
camptothecin were initiated in the late 1960s using an analog
(the sodium salt). Although this compound is quite water soluble,
its anticancer activity is substantially diminished. Clinical
trials were abandoned due to high toxicity and low efficacy,
halting progress of camptothecin for more than a decade until
its unique mode of action was discovered in 1985.
Learned: Early Years of Taxol Research
of the early observations noted by Drs. Wall and Wani during
their work with C. acuminata was a strong correlation between
in vitro cytotoxicity and in vivo anticancer activity. Based
on this insight, Dr. Wall requested that RTI be assigned strongly
cytotoxic plant extracts from the NCI. In contrast, other
research groups shunned the cytotoxic extracts, wrongly presuming
that general cytotoxicity would not lead to promising drug
rationale for selecting plants to study is also a story worth
mentioning: with limited funding for gathering samples, NCI
chose to focus on sources available in the United States and
on unique plants that had yet to be studied in depth; Taxus
brevifolia met these qualifications. Thus, T. brevifolia,
a species of yew tree that grows in the Pacific United States,
was assigned to RTI for investigation.
1971, Drs. Wall and Wani had succeeded in isolating and determining
the structure of the active compound from T. brevifolia, which
they named taxol. Publication of their results would mark
their sixth paper on a natural product with promising anticancer
activity. Twenty years later, this compound would become a
valuable weapon in the fight against cancer.
Perseverance, and a Late Correction
structural characterization of camptothecin was certainly
challenging, especially given the limited spectroscopic tools
of the day. However, once a crystal suitable for X-ray analysis
was prepared, the structure elucidation moved fairly rapidly.
In contrast, the structure elucidation of Taxol was extremely
difficult. The molecule had to be broken into parts—a
large, complex core and a side chain. Even then, determining
how the pieces were assembled based on X-ray structures of
the parts was not straightforward.
the time, camptothecin was advancing into early clinical trials.
In addition, there were many other promising plants to study,
while Taxol’s structure remained elusive. At one point,
Dr. Wall urged Dr. Wani to move on to other projects and to
work on Taxol only as a low priority. Dr. Wani persisted,
often on his own time, and his perseverance led to success.
RTI researchers determined a tentative structure of Taxol
in late 1970.
one final experiment, as Wani and colleagues attempted to
modify Taxol to increase its potency, they realized that the
tentative structure was incorrect. They had misplaced the
side chain. In the end, skill, determination, and luck came
together for the greater good, and the research team corrected
their error a scant few months before publication.
the Problem of Supply
naturally occurring substances such as Taxol and camptothecin,
the question of supply can become central to their evolution
into commercially available drugs. This is particularly true
for Taxol, whose complex structure renders its total synthesis
supply problem remained until the late 1980s, when researchers
found a way to extract a similar compound from the needles
(a renewable resource) of another species of yew. That compound—10-deacetylbaccatin
III—consisted of the complex core molecule of Taxol
to which researchers successfully combined a synthetic version
of the relatively simple side chain.
Novel Methods, Today’s Best Practice
isolate and characterize both camptothecin and Taxol, RTI
researchers used a then-novel method known as bioactivity-directed
fractionation. In this process, a promising plant extract
is fractionated, and the fractions are tested for activity.
This process is performed iteratively —further purifying
the active fractions and retesting —until the active
compound(s) is isolated.2 Drs. Wall and Wani
also pioneered the use of in vitro cytotoxicity as a predictor
of in vivo efficacy. By using these bioassays to predict whether
plant extracts or natural product compounds would have anticancer
activity, they were able
to focus and accelerate their research toward new treatments.
Today, these techniques are used routinely in natural products
laboratories around the world to discover bioactive compounds
from numerous sources, such as plants, marine life, fungi,
Mechanisms of Action
of natural products research’s greatest contributions
is its ability to identify new ways to attack disease. For
example, Taxol and camptothecin each act on cancer cells in
ways that were unimagined prior to the compounds’ discoveries.
Both compounds inhibit tumor growth differently than all other
known anticancer agents. Camptothecin impedes DNA replication
by trapping a key enzyme, topoisomerase I. In contrast, Taxol
stimulates the development of microtubules causing cells to
be unable to coordinate cell division. Through very different
mechanisms of action, both compounds lead to cancer cell death.
and Camptothecin Today
the decades that followed the initial work of Drs. Wall and
Wani, many researchers would prove instrumental in the development
of successful cancer treatments from Taxol and camptothecin.
Efforts to improve the methods for synthesizing the compounds
and to reduce the side effects associated with the drugs are
Taxol is approved by the U.S. Food and Drug Administration
for treatment of refractory ovarian cancer, metastatic breast
and lung cancers, and Kaposi’s sarcoma, while first-generation
analogs of camptothecin (topotecan and irinotecan) are approved
for treatment of ovarian and colorectal cancer. Today, one-third
of all cancer treatments are derived from work in RTI’s
Natural Products Laboratory. Meanwhile, many other Taxol and
camptothecin analogs are currently undergoing clinical trials
and may yield new cancer-fighting drugs.
recognition of their keen scientific intuition, their perseverance,
and their incontrovertible achievements, Drs. Wall and Wani
have received a number of prestigious accolades, including
the 2000 Charles F. Kettering Prize. The most recent honor—designation
of RTI’s Natural Products Laboratory as one of fewer
than 50 National Historic Chemical Landmarks—is particularly
fitting for a scientific achievement of such singularity.
and camptothecin have prolonged and saved the lives of hundreds
of thousands of cancer patients. Moreover, in the course of
discovering these potent anticancer agents, researchers identified
novel mechanisms of action for killing cancer cells, and the
scientific community benefited from their new ideas and methods
for finding and refining bioactive compounds from natural
resolve and innovation evident in the breakthrough research
of Drs. Wall and Wani is a legacy that persists. Research
into natural products has contributed 65% of today’s
anti-infective and anti-cancer drugs. In fact, fully 25% of
the drugs in use today originated from sources in nature.
Dr. Wani remains an active mentor in RTI’s Natural Products
Laboratory, where investigations in medicinal chemistry continue.
addition to its active research efforts, RTI is working to
ensure the Wall/Wani legacy by endowing fellowships in natural
products research in their name, with the support of the American
Society of Pharmacognosy and other private donors. Building
on the accomplishments of the past 40 years, RTI will keep
its Natural Products Laboratory at the forefront of the field,
through research, mentoring, and fellowships, for the next
four decades and beyond.
authors are all from the Research Triangle Institute, RTP,
NC, USA. Nicholas H. Oberlies <firstname.lastname@example.org>
is a research chemist (Ph.D.) at RTI’s Natural Products
Laboratory, while Sharla Flora and Anna L. Weaver are both
editors/writers for the Institute.
Taxol, a word coined by Monroe Wall, is a registered trademark
of Bristol-Myers Squibb. Camptothecin is a trademark of the
Research Triangle Institute.
In contrast, a phytochemical approach involves isolating numerous
compounds from a plant without regard to bioactivity.
last modified 30 June 2003.
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