In 1966 Monroe Wall wrote of his work at the Eastern Regional Research
Laboratory: The joint effort of chemists and botanists proved to
be a good model for future programs. Indeed, it firmly established the
fact that the close cooperation between chemists and botanists was required
for a successful natural products program.1
Monroe Wall was born in Newark, New Jersey, in 1916 and earned his undergraduate
and graduate degrees from Rutgers University. In 1941 he joined the USDAs
ERRL in Philadelphia where he worked on potential agricultural alternatives
for products, such as rubber, critical to the war effort. After the war,
he became involved in plant screening, and in 1957 a chance visit from
Jonathan Hartwell of the Cancer Chemotherapy National Service Center changed
the course of Walls career.
It was Hartwell who convinced Wall to send NCI one thousand ethanolic
plant extracts for antitumor activity testing. A year later Wall learned
that one of the plants demonstrated potent activity: Camptotheca acuminata.
But the USDA was not interested in anticancer drug research, so Walls
ambition to identify the active component in C. acuminata had to
be put on hold until July 1960 when the Research Triangle Institute recruited
him. According to Mansukh Wani, an organic chemist born in Bombay, India,
who Wall lured to RTI in 1962, the Institute was nothing but four
walls. It was not until the fifth Wall arrived
that the chemistry programs, in the form of the Natural Products Laboratory,
Wani describes Wall as a go-getter and a very dedicated
scientist. About Wall, Wani adds, persistence was his greatest
virtue, but patience was not. Wall and Wani collaborated for forty
years, a collaboration that began with research into the nature of the
compounds responsible for the antitumor activity in C. acuminata.
By 1963 RTI had an approximately 20 kg sample of the wood and bark of
C. acuminata available, and Wall and Wani and colleagues at RTI
began what they describe as bioactivity-directed fractionation.
In this the crude plant extract is purified in an iterative manner. At
each stage the fractions are tested for bioactivity. Those
fractions showing the most potent activity are carried on to the next
stage of purification. The process is repeated many times until the compound(s)
responsible for the bioactivity observed with the crude extract are isolated.
In the 1960s this was a difficult and slow process requiring great skill
and intuition on the part of the researchers using equipment that can
now be found only in museums.
By the time Wall and Wani began fractionating their samples it was known
that C. acuminata was very active in the L1210 mouse leukemia assay,
which was unusual since most plants did not exhibit such activity. It
was this activity that had aroused the interest of NCI. All of the fractions
of the extract were analyzed both by the in vivo L1210 mouse life
prolongation assay and by the KB in vitro cytotoxicity assay. The
pure compound isolated as a result of the fractionation was given the
name camptothecin and it was shown to be the agent that was not only very
active against L1210 leukemia but also against P388 leukemia cells.
RTI scientists Keith Palmer and Harold Taylor did the original isolation
of camptothecin, and Ed Cook worked on determining its structure. At that
point, Wall asked Wani, who he described as having the knack to
work on small amounts of material, to prepare a camptothecin derivative
for single X-ray crystallography. The derivative was sent to Andrew McPhail
and George Sim at the University of Illinois who reported back within
a few weeks the tentative structure of camptothecin, which is unusual
although it is related to the indole alkaloids. The research on the isolation
and structure of camptothecin was published in 1966 in the Journal
of the American Chemical Society, the first paper Wall, Wani, and
colleagues published on a natural product with anticancer potential. Wani
describes the isolation of camptothecin as the most exciting scientific
event in my life.3
Because camptothecin showed such promising antitumor activity, the NCI
decided to proceed with clinical trials. But camptothecin is not soluble
in water (which makes delivery of a potential drug difficult) so the trials
were conducted with a water-soluble sodium salt that could be formulated
for intravenous delivery. In the trials, some patients with gastrointestinal
tumors responded to treatment for a short time.
Despite some encouraging successes, the use of camptothecin as an anticancer
agent languished for almost fifteen years until its unique mode of action
for killing tumor cells was determined. Camptothecin traps an important
cellular enzyme, topoisomerase I, in complexes with DNA. This prevents
cancer cell DNA replication and results in the death of the cancer cell.
This unique mode of action rekindled interest in developing analogs of
camptothecin that were both water soluble and retained anticancer activity.
In the mid-1990s, two camptothecin analogs, topotecan and irinotecan,
received FDA approval for use against ovarian, lung, breast, and colon
Wall and Wani worked with many plant samples in the 1960s in addition
to C. acuminata. One of these samples came from the bark of Taxus
brevifolia, a tree that was to have a much more convoluted history
in the annals of drug development than C. acuminata, but which
would eventually yield one of the most potent chemotherapy agents yet
1 Wall, Monroe and Mansukh Wani, Camptothecin: Discovery
Annals of the New York Academy of Sciences, Volume 803, December
13, 1996, p. 1.
2 Interview with Dr. Mansukh Wani conducted by Judah Ginsberg
on January 13, 2003.
3 Ibid. Wall, M. E., M. C. Wani, C. E. Cook, K. H. Palmer,
A. T. McPhail and G. A. Sim, 1966, Plant antitumor agents. 1. The
isolation and structure of camptothecin, a novel alkaloidal leukemia and
tumor inhibitor from Camptotheca acuminata.
Journal of the American Chemical Society. 88: 3888-3890.