To clone the genes, the researchers snipped the genome of the bacteria (Actinosynnema pretiosum) into small bits to create a genomic library. They used a gene that already had been cloned from another microorganism (Amycolatopsis mediterranei) as a reference to screen the library and find the genes needed for maytansinoid construction. Having access to the genes that control the formation of maytansinoids allows scientists to manipulate the structure of the anti-cancer agent at the DNA level.

The work, for which the UW has applied for a patent, allows for a detailed analysis of maytansinoid formation at both the genetic and biochemical levels. It also sets the stage to modify maytansinoids through genetic engineering, so they are less toxic to humans, are more effective against cancer and bond easily with delivery agents.

Several companies are in discussions about the possibility of using the research to combine maytansinoids with antibodies that target tumors. The antibodies would search out specific cancer antigens attach only to cancer cells, Yu said. The maytansinoids then can enter the cancer cells and destroy them without damaging surrounding healthy tissue.

"It is a warhead strategy," he said.

The work has provided researchers with a number of options other than simply deciphering the biosynthesis of pre-existing compounds, Yu said. Manipulating the structure, he said, ultimately could lead to development of more effective cancer drugs.

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Contact: Vince Stricherz
vinces@u.washington.edu
206-543-2580
University of Washington
10-Jun-2002