OHSU

Gleevec Protects Mice from Major Cause of Heart Disease

04/10/03   Portland, Ore.

Drug developed by OHSU researcher reduces effects of atherosclerosis in genetically engineered mice

Gleevec protects mice from atherosclerosis even when they are fed a high-cholesterol diet. Gleevec was found to have a "profound protective effect" on these genetically engineered mice susceptible to atherosclerosis, the buildup of cholesterol and fatty substances in blood vessels. Atherosclerosis is a major cause of heart disease and can lead to heart attack or stroke. The findings were part of a study conducted by researchers at the University of Texas and published in the April 11, 2003, issue of Science.

"Heart disease is the leading cause of death, with cancer coming in a close second, so progress in understanding these diseases is exciting," said Brian Druker, M.D., JELD-WEN Chair of Leukemia Research at Oregon Health & Science University Cancer Institute and a Howard Hughes Medical Investigator. Druker, in collaboration with scientists at Novartis, helped develop Gleevec to target the molecular cause of chronic myelogenous leukemia. "However, as intriguing as these results are, whether they will translate into benefits for people will require many years of research in clinical trials."

The body attempts to repair weakened blood vessels by sending a growth factor to promote smooth muscle cells at the damaged site. While investigating the role of a protein called LRP1, the University of Texas researchers found LRP1 stops the production of smooth muscle cells before too many are produced and atherosclerosis ensues. They also discovered that Gleevec can substitute for LRP1.

In mice genetically engineered not to have any LRP1, the growth factor malfunctioned. An excess of smooth muscle cells accumulated and the vessel wall became highly susceptible to cholesterol buildup and atherosclerosis. Inactivating LRP1, the researchers discovered, increased the likelihood of developing the disease.

Because Gleevec is known to turn off the growth factor that stimulates smooth muscle cell production, the researchers fed a high-cholesterol diet mixed with Gleevec to the genetically engineered mice for six weeks. Gleevec behaved like LRP1 in the mice, restraining the proliferation of too many cells. This significantly reduced vessel abnormalities that lead to atherosclerosis.

In 2001 the Food and Drug Administration broke a record for cancer therapy approval by fast-tracking Gleevec, approving it in less than three months for patients who failed interferon treatment. In 2002 the FDA approved Gleevec as an effective treatment for gastrointestinal stromal tumors, a deadly form of intestinal cancer that, until then, had been difficult to treat. Recent studies also have found Gleevec to be effective in treating hypereosinophilic syndrome, a rare and often fatal blood disorder.

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