CHAPEL HILL - University of North Carolina at Chapel Hill scientists believe they have discovered a major reason why muscles often decay in patients with cancer, AIDS, late-stage heart disease, severe burns and numerous chronic diseases. Their research focuses on cachexia, an important syndrome they say doctors know well but which is largely unfamiliar to lay people, and could lead to an effective treatment for the condition.
Cachexia, which kills an estimated one third of cancer patients, results from activation of a factor known as NF-kappa B, the new experiments show. NF-kappa B, a natural substance that attaches to DNA inside cell nuclei and turns genes on and off like a switch, prevents expression of a key regulatory protein called MyoD from replenishing muscle tissue as it does in healthy people.
A report on the work appears in the Sept. 29 issue of Science. Authors, all of the UNC-CH School of Medicine's Lineberger Comprehensive Cancer Center, are postdoctoral fellows Denis C. Guttridge, Marty W. Mayo and Cun Yu Wang, as well as Dr. Albert S. Baldwin Jr., a biology professor. Graduate student Lee V. Madrid of the Curriculum in Genetics and Microbiology also helped with the research.
"Cancer cachexia, which causes patients to waste away, literally, has been documented for at least 100 years, but it wasn't until about 20 years ago that researchers discovered a cytokine protein called tumor necrosis factor and that the factor could elicit cachexia," Guttridge said. "What we have done is to identify a key part of what's happening mechanistically inside muscle cells to cause cachexia."
The UNC-CH experiments, which involved both cultured mouse muscle cells and muscle in live mice, clearly implicated NF-kappa B as a destructive link between tumor necrosis factor and MyoD, he said. When NF-kappa B is either absent or inactivated, muscle cells containing MyoD develop and grow normally.
"When you see cancer patients becoming very frail and weak even though they are getting plenty to eat, what is happening is that they are losing skeletal muscle and becoming more susceptible to other problems," Guttridge said. "We've had physicians tell us that if they could just make their cancer patients a little stronger and healthier, those patients would have a much better chance of responding to chemotherapy and fighting infections, as well as improving their quality of life."
Tumor necrosis factor is one of the cytokines the body produces naturally in immune cells as a defense mechanism in response to tumors, severe burns and infections, he said. In those serious illnesses, levels of tumor necrosis factor are elevated. The experiments show that tumor necrosis factor activates NF-kappa B, which in turn activates another factor that suppresses MyoD.
"NF-kappa B now becomes a very attractive new therapeutic target for preventing cachexia," Guttridge said. "This is exciting, and we've gotten nothing but very positive feedback from colleagues around the country."
Baldwin, Guttridge's mentor, said that on a scale of one to 10, the new findings could rate a 10 in importance based on the novelty of the findings and their potential.
"We're not saying that this is the only mechanism associated with cachexia, but we believe that it is a very important one, possibly the most important," he said. "Since we now know how to inhibit NF-kappa B, and we're getting better at it every day, this will lead to therapies for reducing cachexia, which may well lead to significant improvement in the quality of life of patients who have chronic diseases like cancer and AIDS."
The next step will be to test possible therapies in animal models of cachexia, Baldwin said.
Support for the continuing studies came from the National Cancer Institute and the National Institute of Allergy and Infectious Diseases.
Note: Guttridge and Baldwin can be reached at (919) 966-3652 or via email: jhall@med.unc.edu .
Lineberger Comprehensive Cancer Center: Dianne Shaw, 966-5905 News Services Contacts: Karen Moon, 962-2091 (broadcast), David Williamson, (919) 962-8596.
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