Cancer Drug Gleevec Could Fight Stroke

MONDAY June 23, 2008 -- A powerful weapon against cancer might also boost stroke patients' survival, new research suggests.

Gleevec, long hailed as a "wonder drug" against cancers such as chronic myelogenous leukemia (CML), will be tested to see if it can boost the effectiveness and limit the side effects of the clot-dissolving drug tissue plasminogen activator (tPA), an international team of researchers say.

One of the ways that Gleevec stops the growth of cancer cells is to block receptors of platelet-derived growth factor-CC (PDGF-CC), explained Daniel Lawrence, professor of cardiovascular medicine at the University of Michigan and a member of the research team.

Studies performed at his lab, as well as at Sweden's Karolinska Institute, have both shown that blocking those receptors improves the activity of tPA.

Doctors typically give tPA in the hours after an ischemic stroke, which occurs when a blood clot blocks a brain artery. About 80 percent of all strokes are ischemic, and tPA is given to dissolve the clots.

But there's a big downside with the drug: It also can increase the odds for brain hemorrhage.

Reporting in the June 22 online edition of the journal Nature Medicine, the researchers at Karolinska and in Michigan showed for the first time that tPA increases the risk of bleeding by acting on PDGF-CC, as well as the cellular receptor to which it binds. This activity makes blood vessels in the brain dangerously leaky.

However, in other laboratory tests and in animal studies, Gleevec prevented this leakiness by blocking PDGF-CC receptors.

"Blocking the receptor reduces formation of edema -- swelling of the brain -- and so even in the absence of tPA, the [Gleevec] treatment would be beneficial," Lawrence pointed out.

But Gleevec might also extend tPA's usefulness, he added. "tPA loses its efficacy three hours after a stroke. Part of that loss may be an increase in major side effects, and the major side effect of tPA is bleeding," Lawrence explained. "You could conceivably block the receptor and give tPA beyond its current three-hour limit and still be effective at removing the blockage of a brain artery but reduce the complications."

Gleevec is not necessarily the perfect drug to achieve that effect, Lawrence said, because its activity on a number of other receptors could raise new concerns. "We are not currently testing any [other drug] in our laboratory, but any drug that blocks those receptors might possibly be even better than Gleevec," he said. "One could develop even more specific receptor blockers."

A first human trial, primarily to test the safety of the proposed treatment, will soon begin in Sweden, said Ulf Eriksson, professor of molecular biology at the Karolinska Institute, one of the leaders of the research effort. It will be done by physicians at the Karolinska Institute Hospital in Stockholm.

The trial is planned to include 60 people who will be treated in the hours after they suffer strokes. Some will be given Gleevec within three hours of the stroke in addition to standard tPA treatment. Others whose treatment started later for one reason or another will be given Gleevec in addition to tPA after the three-hour period desired for such treatment. Their results will be compared to similar stroke patients given standard treatment.

Results of that study should be available "within one year," Eriksson said. Plans for future human trials would depend on those results, he said.

More information

There's more on tPA and other stroke therapies at the American Heart Association.

Posted: June 2008


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