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The sedative was given to pregnant women in the 1950s and 1960s to treat morning sickness until it was found to cause birth defects – mostly deformities to the arms or legs. It is currently used as a treatment for the blood cancer known as multiple myeloma.
Shaughnessy, director of the Lambert Laboratory of Myeloma Genetics in the Myeloma Institute for Research and Therapy (MIRT) at UAMS, and his colleagues found that the drug interfered with limb development by setting off a chain of reactions among a series of proteins tied to bone development. Thalidomide-induced damage was reduced when these reactions were blocked, according to the researchers. The identification of the molecular reactions elicited by the drug also could lead to new cancer treatments.
The article, “Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway,” will be published in the May 2007 issue of The FASEB Journal, the journal of the Federation of American Societies of Experimental Biology. The article is now available online at http://www.fasebj.org/.
“It’s an important discovery as it potentially solves the mystery behind the thalidomide birth defect link,” said Shaughnessy, who also is a professor in the UAMS College of Medicine. “Since thalidomide and its derivatives are also used to treat cancer, the discovery also gives us another lead in our search for more effective cancer treatments.”
The study was co-authored with Jurgen Knobloch and Ulrich Ruther, both of the
Previously, it was believed the thalidomide-induced birth defects were caused by DNA and cell damage caused by a high-level burst of chemicals known as oxygen free radicals, Shaughnessy said. Another theory was that the drug was changing the way molecules held developing cells together.
Through molecular analysis, the researchers found that the free radicals caused production of a protein called Bmp, or bone morphogenic protein. Bmp then transmitted a signal in cells of the developing limb that activated production of another protein, called Dickkopf 1 (Dkk1). Dkk1 is a natural blocker of the molecule Wnt, which is essential for normal bone growth and development. The data suggests that the blockage of this pathway leads to the inhibition of bone development and limb growth.
Bart Barlogie, M.D., Ph.D., director of the MIRT and a professor in the UAMS College of Medicine, pioneered the use of the once-banned thalidomide as a treatment for multiple myeloma in the late 1990s. Thalidomide was tried initially in the case of unresponsive disease because of its suggested anti-angiogenic properties – meaning that it blocks the development of blood vessels that form to supply blood to tumor cells and thus kills through an indirect mechanism.
A team of UAMS researchers, including Barlogie and Shaughnessy, reported in the New England Journal of Medicine in 2006 that thalidomide as a part of a treatment program for multiple myeloma produced higher remission and five-year survival rates in patients. The drug failed to increase overall survival and was associated with several adverse side effects, such as blood clots, according to the research.
Shaughnessy said the molecular pathway used by the drug to produce the birth defects could also be the mechanism that makes it effective against multiple myeloma.
“If true, the identification of the mechanism for thalidomide-induced birth defects may turn a tragic story into one of hope,” Shaughnessy said.
Myeloma, also called multiple myeloma, is the second largest of the blood cancers, affecting an estimated 750,000 people worldwide.
UAMS is the state’s only comprehensive academic health center, with five colleges, a graduate school, a medical center, six centers of excellence and a statewide network of regional centers. UAMS has about 2,430 students and 715 medical residents. It is one of the state’s largest public employers with about 9,400 employees, including nearly 1,000 physicians who provide medical care to patients at UAMS, Arkansas Children’s Hospital, the VA Medical Center and UAMS’
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