[Editors] MIT: Plant's synthesis produces cancer drugs

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
Phone: 617-253-2700
http://web.mit.edu/newsoffice/www

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Periwinkle can serve as tiny chemical plant

Researchers enhance periwinkle plant's biochemical pathways
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For Immediate Release
THURSDAY, NOV. 16, 2006
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

PHOTO AVAILABLE

CAMBRIDGE, Mass.--MIT researchers have discovered a way to manipulate 
the chemistry taking place in the tiny periwinkle plant to produce 
novel compounds that could have pharmacological benefits.

"Plants are really nature's best chemists," says Sarah O'Connor, the 
Latham Family Career Development Assistant Professor of Chemistry and 
co-author of a paper on the work in the Journal of the American 
Chemical Society.

O'Connor and chemistry graduate student Elizabeth McCoy decided to 
explore the periwinkle plant in part because it is the only plant 
that produces vinblastine, a drug widely used to treat cancers such 
as Hodgkin's lymphoma.

The biochemical pathway that produces vinblastine and other alkaloid 
compounds is long and complicated, usually requiring at least 10 
enzymatic steps, which occur in different parts of the periwinkle 
plant (also known as Catharanthus roseus).

O'Connor and McCoy essentially tricked the plants into producing new 
compounds by feeding them slightly altered versions of the normal 
starting materials (tryptamines) for alkaloid synthesis.

"You can make a great number of modifications of simple starting 
materials, and the plants incorporate those starting materials into 
the biosynthetic pathway," said O'Connor.

Alkaloids are believed to have a protective function for plants 
because they are toxic to bacteria and herbivores who try to eat the 
plants. This theory is bolstered by the fact that the reaction 
products move closer to the plant surface as they move through the 
biosynthetic pathway, said McCoy.

Vinblastine, which has been used as a cancer drug since the 1960s, is 
very difficult to isolate from the periwinkle plant because it is 
produced in minute quantities (the yield is about 0.002 percent of 
the plant's weight). However, it would be even more difficult (and 
expensive) to synthesize vinblastine in the laboratory.

"It's a beautiful and elegant synthesis, but it's not cost-effective, 
so industry does not currently use synthesis to make vinblastine," 
said O'Connor.

Other researchers are now running clinical trials for artificial 
analogues of vinblastine, so it could be beneficial if periwinkle 
plants could be induced to synthesize those same compounds or new 
compounds that might be even more effective.

Because it is easier to make modifications to the starting materials 
than the end product, the researchers' method could produce a diverse 
array of alkaloids to test for potential drug activity. "You can only 
make a limited number of modifications to natural products that are 
already synthesized," O'Connor said.

In their recent paper, the researchers describe 18 new products, but 
there are many more possibilities. "There's no end to what you could 
do to modify the starting materials," said McCoy.

Scientists often engineer bacteria and yeast to produce desired 
compounds, such as antibiotics, but few have tried it with plants, 
because their biochemistry is so complex.

"Plants are the hardest to work with, so people have avoided looking 
at plant biosynthetic pathways," O'Connor said.

The research is funded by the Smith Family Medical Foundation, 3M, 
the Beckman Foundation, the American Cancer Society and the American 
Chemical Society.

--Written by Anne Trafton, MIT News Office--