Take It from Plants
by David Vander Velde with Roger Martin
Those
who search for drug molecules often take a hint from plants (which can't
run down to the pharmacy when they catch something and so must keep
protective molecules in stock).
When researchers discover a promising molecule, called
a drug lead, in a plant, they'll tinker with nature's version in order
to improve it.
That's the story of a cancer-fighting drug called taxol.
It was discovered in the early 1970s as a result of
a National Cancer Institute screening of many plant species in a search
for those with anticancer activity. It has proven extremely useful in
treating breast, ovarian, lung and neck cancer.
The original source of the drug, the Pacific yew tree,
would have been driven to extinction by efforts to collect enough of
its bark to make medicine for use by cancer patients. (Taxol is thought
to be part of the plant's defense system against browsing animals.)
Fortunately, synthetic organic chemists have solved the supply problem.
They have found ways to make the drug molecule from two components.
A simpler, inactive piece of the molecule, baccatin III, can be extracted
from foliage clippings of cultivated yews. (The companies keep yew plantations
with millions of young trees; the removal of the clippings doesn't harm
the plant.) This part is then joined to a more readily synthesized part
(a phenylisoserine sidechain).
Two forms of taxol are currently marketed. They are
Taxol® itself, made by Bristol-Myers Squibb, and Taxotere®,
by Rhone-Poulenc Rorer. A number of related compounds -- generally called
taxoids -- are in clinical trial or development.
Chemists and biologists at many universities and pharmaceutical
companies around the world have contributed to our present understanding
of how these molecules kill rapidly dividing cancer cells. That understanding
is still incomplete, and parts of it are being debated among scientists.
What has been established is that taxoids bind to a
protein called tubulin that's inside cells. That protein is an ingredient
of structures called microtubules that are essential for cell division.
After microtubules have finished their role in cell division, they're
supposed to break apart. But the taxoids prevent that. Thus, the cancer
cell can't finish dividing and, in a matter of hours, dies.
Just in the past two years, scientists at the University
of California in Berkeley have given us our first molecular-level look
at tubulin, taxoids sticking to tubulin and microtubules. We're now
working to refine the picture.
For the past decade, several KU professors, doctoral
students and postdoctoral fellows have been working on various aspects
of the chemistry and biochemistry of taxoids.
Gunda Georg, a professor of medicinal chemistry, has
applied her knowledge of how to construct antibiotic molecules to synthesizing
both the part of the taxol molecule that's found naturally in yew clippings
and the custom-designed sidechains. Some of her compounds are more active
than Bristol-Myers Squibb's product.
Meanwhile, Richard Himes, a professor of molecular
biosciences, has been studying the tubulin protein for much of his career.
Students in his laboratory have helped to determine the potency of the
synthetic, cancer-killing taxoids made in Georg's laboratory.
An exciting recent development in this area has been
the discovery, by Georg; Mary Lou Michalis, a professor of pharmacology;
and their co-workers that taxoids can protect brain cells from damage
by amyloid, the waxy substance that some think causes Alzheimer's disease.
At least this protection holds with cells experimented upon in lab dishes;
the work of verifying this finding in laboratory animals and humans
remains to be done.
This work raises the hope that someday, people at risk
of developing Alzheimer's disease could ward off the disease by taking
medication before they show any symptoms or have lost any mental function.
One of the principal problems is getting the drug into
the brain. In terms of defense from invasion or intrusion, the brain
and eye are, among the body's organs, unsurpassed. Even so, Ken Audus,
a professor of pharmaceutical chemistry, has for some time been studying
the barrier that exists between the bloodstream, a convenient route
of delivery for the Alzheimer's drug, and the brain.
Interested in knowing more about the taxol molecule?
Here's an overview.
What's it like to undergo Taxol treatment? What's it like to undergo
taxol treatment? Find out at the Bristol-Myers
Squibb Taxol site.
