July 29, 2014

   A Publication of the James Buchanan Brady
   Urological Institute Johns Hopkins Medical Institutions

Volume V, Winter 2000
Blocking Endothelin: Targeting Pain, and Cancer Itself?

Urologist Joel Nelson, M.D., has learned a lot about endothelin over the last few years: He was the first to link this chemical -- made by endothelial cells, which line blood vessels -- to the excruciating, debilitating pain that comes when prostate cancer invades the bone. He also tied endothelin to the unique bone damage found in some men with prostate cancer, in which the bone becomes unnaturally thick and rock-hard. And his idea that thwarting endothelin might ease terrible pain -- which, for years, was simply assumed to be an inevitable part of the grim package of "bony metastases" -- has led to the first clinical trials of a new endothelin-blocking agent, called an endothelin receptor antagonist.

But it may be that Nelson has only scratched the surface: Endothelin may turn out to be an even bigger behind-the-scenes player in prostate cancer that anybody realized. And it just might be that blocking endothelin can alter the course of prostate cancer itself.

Endothelin is a vasoconstrictor, the most powerful one ever discovered. It is found in the bloodstream: In a heart attack, endothelin is one of several chemicals that cause an artery to spasm, or slam shut -- cutting off the supply of blood and oxygen to tissue, resulting in terrible, sometimes crushing pain. But endothelin's concentrations are highest -- about 500 times greater -- in semen; part of this fluid is contributed by the prostate.

Chemically, endothelin bears a striking resemblance to snake venom, and to apamin -- "the compound that hurts so much when you get stung by a bee. Endothelin is painful when it's given in the right doses to humans," says Nelson. "Is it possible that some of the bone pain that men experience in advanced prostate cancer is because the cancerous cells are secreting something which is very similar to snake venom?" And is it possible to spare patients this terrible ordeal by cutting off the supply of endothelin?

So far, the early clinical trials of the endothelin-blocking agent Nelson helped design -- any trials of a new drug must first prove that it does no harm, and to find a dosage that's safe for patients to take -- have found that "the drug is very safe, very well-tolerated," Nelson says. The drug, given to men and women with advanced cancer that had metastasized to the bone, did indeed seem to relieve pain, as measured by a significant decrease in patients' need for morphine or similar painkillers. (However, because there was no "control" group of patients taking placebos in these early studies, Nelson cautions that further studies are needed to determine just how effective the enothelin- blocker is in easing pain.) "If we can improve this terrible pain and make people feel better, we can make a major improvement in quality of life for these patients, Nelson says.

But he hopes for even more. The healthy prostate makes endothelin; the cancerous prostate does, too, even during hormone therapy -- and this is of great interest to Nelson. Because endothelin is impervious to hormones -- just like the hormone-insensitive cells in advanced prostate cancer -- is it possible that blocking endothelin can also somehow slow the growth of cancer, and prevent its damage? In laboratory studies, he and colleagues found that cancerous mice with higher levels of endothelin developed significantly more new bone growth (similar to the bone changes found in men with advanced prostate cancer) than other mice -- and mice given an endothelin-blocker seemed to be protected against this growth.

The early clinical trials of the endothelin-blocker produced another exciting finding: A drop in PSA levels in 68 percent of men with prostate cancer. In some men, this decline was small -- a decrease, for example, from 800 to 780. But in other men, PSA levels plummeted: One man's PSA shot down from 880 to 440 within a week; in two men, the PSA drop was nearly 90 percent. (It may be that some prostate cancers -- which are notoriously variable in their makeup of cells, and their susceptibility to various forms of treatments -- contain more endothelin, or are more affected by an endothelin-blocker than others. If this proves true, perhaps scientists can one day predict who will be most greatly helped by this kind of drug.)

The next step is to find out whether the endothelin-blocker can go the distance in fighting the cancer itself. Already, Nelson's laboratory work has shown that endothelin inhibits cell death -- that cells given endothelin are less vulnerable to chemotherapy, that they don't die as readily as other cells. "Obviously, we'd like cancer cells to die," he says. "If we can block endothelin's ability to let cancer cells survive, it may increase the effects of chemotherapy or hormonal therapy."

"New Bone Formation In An Osteoblastic Tumor Model Is Increased By Endothelin- 1 Overexpression and Decreased by Endothelin A Receptor Blockade," Urology, Vol. 53, No. 5 pp. 1063-1069. 1999.


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