Endothelin

The bone pain that can come with advanced prostate cancer is particularly horrible -- a nightmare of disabling torment worthy of Dante that, at its worst, defies just about every painkiller except morphine.

Why is it so bad? For years, although there have been many attempts to manage this pain better, no one asked this question; the assumption was that extreme pain was simply an inevitable part of the grim package of "bony metastases," cancer that invades bones.

But urologist Joel Nelson, M.D., has another theory: That this pain is caused by one of the body's own chemicals, called endothelin (made by endothelial cells, which line blood vessels). Endothelin is a vasoconstrictor (a substance that causes blood vessels to contract), "the most potent one ever discovered," says Nelson.

Although it's found in the bloodstream, endothelin's concentrations are highest -- about 500 times greater -- in semen; part of this fluid is contributed by the prostate. The healthy prostate makes endothelin; the cancerous prostate does, too -- even during hormone therapy, when the prostate's supply of male hormones is shut off. (For more on hormone therapy, see related story.)

Because endothelin is impervious to hormones -- just like the hormone-insensitive cells in prostate cancer -- "to my way of thinking, it's exactly what we should be studying," says Nelson, "because patients who die of prostate cancer don't die of hormone-sensitive disease."

Endothelin, as it turns out, can be a nasty customer: On a molecular level, it bears an amazing structural resemblance to snake venom. "This particular snake venom is painful," says Nelson, "and so is endothelin when it's given in the right dose to humans. In fact, endothelin has a lot of similarity to a toxin we've all experienced -- apamin, the compound that hurts so much when you get stung by a bee."

Which begs the question: "Is it possible that some of the pain that men experience when they have advanced prostate cancer in their skeleton is because the cancerous cells are secreting something which is very similar to snake venom?"

Even more intriguing: In addition to the terrible pain, men with prostate cancer are often plagued by other bone problems. In some men, the cancer erodes bones, making them riddled and fragile. But in other men, the bones seem to turn to concrete; they get unnaturally thick and hard. Here, the prostate cancer cells apparently secrete something that serves, in effect, as a coat of super-hard lacquer. Endothelin may play a role in this development.

Nelson believes that if endothelin could somehow be blocked, these changes might be prevented. This spring, he will begin the first clinical trial of an endothelin-blocking agent in cancer. Ideally, the study will find that stifling endothelin accomplishes two things -- that it will not only thwart bone damage, but bring desperately needed pain relief.

Endothelin's contributions to pain are complex, Nelson has learned: For one thing, it can act as a neurotransmitter, a chemical signal to the brain, "so it can activate the normal pain pathways," he says. "But the thought is that by releasing endothelin locally, the cancer cells are also stimulating the nerves sitting right next to them, and that is what's causing the (major) pain. Undoubtedly, there's also some pain from the destruction of the bone, as well."

And, local poison aside, don't forget endothelin's impressive credentials as a vasoconstrictor -- one of several chemicals activated in a heart attack, causing the blood vessels to spasm, or clamp shut. It may also be, Nelson speculates, "that some of the pain these men experience is due to ischemia -- just like angina or heart attack." When the supply of blood is suddenly shut off, oxygen-starved tissue immediately reacts with a cry for help -- impossible-to-ignore, severe pain.

Layer after layer of pain What's happening here? As in so many aspects of cancer, a switch has gone awry. In molecular studies, Nelson and colleagues have discovered that a crucial "on-off" switch -- a receptor that allows the body to control endothelin -- vanishes when a prostate cell becomes cancerous, leaving behind only an "on" switch. If the on-off switch, like the floorboard of a car, has a gas pedal as well as a brake, this receptor seems to malfunction like a stuck accelerator: It's a switch that turns on and stays on, and only increases the voltage each time it's activated.

Men interested in participating in this study should call its principle investigator, Dr. Michael A. Carducci, at (410) 955-8964.

Further Reading

"Identification of Endothelin-1 in the Pathophysiology of Metastatic Adenocarcinoma of the Prostate," Nature Medicine, Vol. 1, No. 9, pp. 944-949, September 1995. Joel B. Nelson, Sean P. Hedican, Daniel J. George, A.H. Reddi, Steven Piantadosi, Mario A. Eisenberger and Jonathan W. Simons.