Selective inhibitor can target specific enzyme that promotes cancer

June 28, 2000

Molecule designed to arrest tumor growth and spread

A selective molecule able to target specific enzymes that help spread cancer may stop the development of some tumors, according to research presented in the July 19 edition of the Journal of the American Chemical Society, published by the world's largest scientific society.

The molecule is able to selectively inhibit gelatinases, enzymes involved in the growth and spread of cancerous tumors, according to Shahriar Mobashery, Ph.D., who headed the research team at Wayne State University in Detroit. It represents the first success in designing a molecule that can specifically target the enzymes that helps tumors to spread. Potential applications include treatment of tumors found in breast and prostate cancers, he said. Based on further research, the inhibitor also may apply to other cancers and inflammations.

Gelatinases are part of a family of proteins known as matrix metalloproteinases, or MMPs, which are responsible for tissue growth, among other things, in plants and animals. Examples of MMP activity range from the healing process after you get a paper cut to the growth of a fetus inside the womb. Cancerous tumors, however, use MMPs to supply themselves with the blood needed for survival and to aid the spread of tumor cells throughout the body.

Since gelatinases help supply blood to tumors, the inhibitor is designed to prevent the blood flow without stopping the normal functions of other MMPs, Mobashery said. The current research is still in the pre-clinical testing stage, meaning much more testing is needed to determine a delivery system and dosage of any possible drug.

Because MMPs are necessary to many functions in the human body, stopping the actions of a select few that have harmful effects has been the goal of many research teams. Other attempts at creating similar drugs have failed because they have not able to target a specific enzyme, Mobashery said.

"We have shown that MMPs can be selectively inhibited," Mobashery said. "The inhibition mechanism is novel and is very good specifically for this certain set of enzymes."

Tumors grow by enhancing the levels of gelatinase in the body, and elevated gelatinase levels have been found to assist the spread of cancerous cells, Mobashery said. The spread of cells throughout the body is the major cause of cancer mortality, he continued.

The new inhibitor molecule mimics a natural inhibitor in the human body that prevents excessive MMP activity, he said. The new molecule is designed to only fit the gelatinase enzyme, and through its design, initiate a reaction that stops the harmful activity, Mobashery said.

Researchers have been aware of MMPs for nearly three decades. There are 26 currently known MMPs in the human body, although developments in genome research should discover more, Mobashery said.

"What we have here is a molecule that shows very high selectivity for inhibition of gelatinase," Mobashery said. "This is the latest in our efforts, and it has turned out to be fabulous."

6/29/00
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The online version of the research paper cited above was initially published June 30 on the journal's Web site. The research was funded by the U.S. Army and the National Institutes of Health.

Dr. Shahriar Mobashery, Ph.D., is the director of the Institute for Drug Design and professor in the Departments of Chemistry, Pharmacology and Biochemistry and Molecular Biology at Wayne State University in Detroit.

A nonprofit organization with a membership of 161,000 chemists and chemical engineers, the American Chemical Society publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio. http://www.acs.org
-end-
The cited research paper is available online at the American Chemical Society's ASAP (As Soon As Publishable) Web site June 30. Journalists desiring access to this site must submit requests in writing to the ACS Department of News and Information or send an e-mail to newsroom@acs.org.


American Chemical Society

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