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Cholesterol lowering Drugs May Delay Growth of Prostate Tumors

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Study links low cholesterol to smaller prostate tumors with fewer blood vessels

February 23, 2009

Boston, Mass. -- Keeping cholesterol levels in check may not only benefit heart health, but may also delay the progression of prostate cancer, suggests a study fromChildren's Hospital Boston. When mice with human prostate tumors were fed a no-cholesterol diet in combination with the cholesterol-lowering drug ezetimibe (Zetia, Schering-Plough), tumor growth was slowed.

The study, published in the March issue of The American Journal of Pathology, also found dramatic reductions in tumor angiogenesis—blood-vessel growth within the tumors—in the mice with the lowest cholesterol levels, suggesting that ezetimibe retards prostate tumor growth at least in part by inhibiting tumor angiogenesis.

The researchers compared four groups of animals--two fed the high-cholesterol diet, with or without ezetimibe, and two fed a no-cholesterol diet, with or without the drug. "We were initially interested to find out whether raising cholesterol would accelerate the rate of tumor growth and whether reducing cholesterol would reduce the growth of tumors," says Keith Solomon, PhD, of the Departments of Orthopedic Surgery andUrology at Children's, and the paper's first author.

Two weeks after tumor implantation, tumors were largest in the animals fed the high-cholesterol diet (averaging 0.88 grams per tumor site), and smallest in those on the no-cholesterol diet plus the drug (averaging 0.63 grams per tumor site).

But there was also a marked difference in angiogenesis. "The thing that caught my attention almost immediately was that when we were harvesting the tumors, there was a great deal more blood in some of the tumors than others," says Solomon. "I didn't even know which groups the tumors were coming from. Then we started to look at this, and found some real group differences that went along with the growth curves."

Staining of the tumors for the endothelial cells that line blood vessel walls showed there was approximately 50 percent more tumor angiogenesis in the untreated high-cholesterol group than in the groups receiving ezetimibe, regardless of which diet they were on. Higher levels of cholesterol correlated with increased angiogenesis.

"This was something we did not anticipate at the beginning of this study," says Solomon. "We hypothesized that the tumors would be bigger or smaller based on the diet and the drug, but we did not hypothesize that it would be related to the degree of angiogenesis."

"The anti-angiogenic effect of cholesterol lowering implies that these findings may have relevance to other tumor types, " says Michael Freeman, PhD, of Children's Department of Urology, senior author of the study.

Cholesterol is synthesized in all areas of the body, but the prostate makes it at a relatively high rate and loses the ability to control cholesterol levels as the body ages. High-cholesterol diets likely contribute to the excess cholesterol in the aging prostate, and may exacerbate disease incidence and progression, Solomon says. Prostate tumors have been shown to contain significant amounts of cholesterol.

"I would speculate that the cholesterol is giving the tumor cells, and cells in the surrounding environment, material to encourage angiogenesis and growth," explains Solomon. "If you blocked tumor cells from synthesizing and taking up cholesterol, they would die. Without cholesterol, there is no growth."

Prostate cancers are usually very slow-growing and many men can live for many years with prostatic tumors before dying of unrelated causes. Solomon speculates that if people aggressively manage their cholesterol levels throughout their lives, it might delay first appearance of medically significant prostate disease by approximately 10 years and may even reduce their appearance overall.

"A 20 to 30 percent reduction in cholesterol might not affect a fast-growing tumor, but could have a significant effect on a slow-growing tumor," says Solomon. "It could mean that men who now have to undergo procedures may be able to avoid irritating, painful, and stressful treatments. It could save lives, money and quality of life because once men have surgery to remove their prostate, they are often left impotent and incontinent."

Population studies have linked prostate cancer with high cholesterol levels and Western diets high in cholesterol. In 2005, the Solomon and Freeman groups showed that cholesterol helps prostate tumors survive and grow at the cellular level by altering chemical signaling patterns.

The researchers now hope to further explore the relationship between cholesterol and its role in prostate tumor angiogenesis and growth. "This has important implications not only for treatment of prostate tumors but also for the treatment of other cancers," says Solomon.

The study was funded by the National Institutes of HealthM and the US Department of Defense.

Contact:
Rob Graham
Children's Hospital Boston
617-919-3110
rob.graham@childrens.harvard.edu

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit:www.childrenshospital.org/newsroom.

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