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Endothelin: Still Beyond Reach

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About the same time that scientists began publishing the disappointing results of trials on congestive heart failure, Clozel of Actelion Pharmaceuticals started testing an endothelin receptor antagonist, bosentan, in animal models of a rare lung disease called pulmonary arterial hypertension, or PAH. Early research suggested that endothelin might play a role in PAH, which kills about 16,000 people every year in the United States. (In PAH, the walls of the small vessels throughout the lungs thicken and stiffen, raising blood pressure and increasing pressure in the pulmonary artery supplying those capillaries. This overworks the heart’s right ventricle, causing lethal damage. Although PAH can be caused by a genetic defect, many cases arise from unknown origins.)


Guy Billout

Studies had shown that ET-1 levels are elevated in the blood and in the lung tissue of people with PAH, and that higher ET-1 levels corresponded to a reduced chance of survival. Clozel wanted to see whether endothelin receptor antagonists could slow or stop the disease. Her studies in rats and pigs showed that blocking the receptors with bosentan made the pulmonary hypertension less severe, and tests in humans demonstrated that keeping endothelin from connecting with ET receptors could prevent, attenuate or even reverse changes in the blood vessels that make it harder for blood to flow through the lungs and lead to suffocation of the heart muscle.

In a series of double-blind, placebo-controlled trials, bosentan improved blood flow in the lungs and increased exercise capacity while slowing the progress of the disease. Longer-term studies found lasting benefits, and patients who take bosentan live longer. In 2001 the U.S. Food and Drug Administration approved bosentan (Tracleer) for treating PAH, and in 2007 it okayed another ET receptor antagonist, ambrisentan (Letairis). A third ET receptor antagonist, sitaxentan, is approved in the European Union, Canada and Australia. In addition, in 2007 bosentan was approved in the European Union for prevention of digital ulcerations (open sores on the fingertips).

Although bosentan and other endothelin blockers have proved to be enormously beneficial to people with PAH, many authors of those 22,000 endothelin papers had something far grander in mind. Yet almost every attempt at treating widely prevalent ET-related disorders has suffered the same fate as the early trials for congestive heart failure.

Consider prostate cancer. In the mid-1990s, researchers found that the cancers known as adenocarcinomas, which include prostate tumors, produce quite a lot of ET. Of course, the same can be said of many cells throughout the body, but ET appears to do many things that are hallmarks of cancer. It encourages cell proliferation, helps new blood vessels supply tumors so the tumors can thrive, and prevents cells from dying on schedule. Endothelin also seems to play some yet-unknown role in cancer pain.

To explore whether ET blockers might have a positive effect in cancer cases, Pittsburgh’s Nelson and his colleagues tested the safety of various doses of the ET receptor antagonist atrasentan in cancer patients in 2002, then the following year completed a placebo-controlled trial of 288 patients. The results were promising, with a slowing of the progression of the disease. Yet larger trials involving patients with metastatic and nonmetastatic prostate cancer found marginal improvements at best. And once again, side effects, including nasal congestion, headaches, edema and heart failure, were an issue. Indeed, the unintended effects of endothelin blockers have been one reason that more of them haven’t made it to market.

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Endothelin’s Trials

Several early trials of endothelin blockers showed no benefit for the treatment of many common conditions, but researchers are holding out hope for these current and soon-to-begin human studies.


1. “A Novel Potent Vasoconstrictor Peptide Produced by Vascular Endothelial Cells,” by Masashi Yanagisawa et al., Nature, March 1988. In the paper that launched the field of endothelin research, Yanagisawa describes his discovery of the most powerful vasoconstrictor ever found.

2. “Pathophysiological Role of Endothelin Revealed by the First Orally Active Endothelin Receptor Antagonist,” by Martine Clozel et al., Nature, October 1993. Researchers describe the precursor to bosentan, the first endothelin-targeting compound to be used in humans, to treat pulmonary arterial hypertension.

3.“Endothelin: 20 Years From Discovery to Therapy,” by Matthias Barton and Masashi Yanagisawa, Canadian Journal of Physiology and Pharmacology, July 2008. The comprehensive review describes this burgeoning field of research, beginning with endothelin’s discovery as a simple vasoconstrictor.

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