"This represents a major contribution to medical science," said Kenneth A. Ault, M.D., Director of MMCRI. "This finding could be ready for widespread clinical use in humans in a very few years."
Thomas Maciag, Ph.D. and his team of scientists at MMCRI's Center for Molecular Medicine led a team of investigators from the Netherlands and Bulgaria, including scientists from Dartmouth Hitchcock Medical Center. They discovered that the function of copper is necessary for restenosis, and that after angioplasty or stent surgery is performed, the presence of copper in cells of the artery enables the regrowth of cells from within the injured vessel. This process recloses the artery in about 30% of cases, requiring more surgery with its inherent expense and risk to the patient.
"Maciag and colleagues appear to have solved a long-lingering paradox in the field of growth factor biology," commented Dr. Elazer R. Edelman, Director of Harvard-MIT Biomedical Engineering Center in Cambridge, Massachusetts. "Their imaginative work may provide novel treatment modalities for a range of critical diseases."
This work was published in a preeminent journal, Proceedings of the National Academy of Sciences, May 27, 2003, in the paper "Copper Chelation Represses the Vascular Response to Injury."
The scientists at MMCRI found that the commonly available reagent TTM (tetrathiomolybdate), which is a specific copper chelator, stopped inflammation and growth of the unwanted new tissue responsible for narrowing of the arteries. TTM was able to inhibit the intracellular function of key regulators of cell growth which normally enable cells to respond to stress. Essentially, chelating copper makes the cells stress resistant.
Understanding the biochemical pathways of cellular response to stress or injury may lead to an alternative and inexpensive treatment to efficiently manage restenosis in humans.
The discovery is the result of approximately fifteen years of basic scientific research. The researchers found that an easily obtained chemical reagent made a direct and simple clinical application suddenly available. The drug TTM is already in use for the treatment of another human disease and, interestingly, has very few and readily reversible side effects.
"Copper Chelation Represses the Vascular Response to Injury"
Lazar Mandinov*, Anna Mandinova*, Stanimir Kyurkchiev, Dobroslav Kyurkchiev, Ivan Kehayov, Vihren Kolev, Raffaella Soldi, Cinzia Bagala, Ebo D. deMuinck, Volkhard Lindner, Marcus J. Post, Michael Simons, Stephen Bellum, Igor Prudovsky, and Thomas Maciag
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME; Institute for Immunology, Sofia, Bulgaria; Department of Physiology, University of Maastricht, The Netherlands; Department of Medicine, Dartmouth Hitchcock Medical Center, Hanover, NH
*Both authors contributed equally to the data presented.
Journal
Proceedings of the National Academy of Sciences