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First Viruses, Now Tumors: AIDS drug shows promise against brain cancers


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Website: http://www.sciencenews.org/20031025/fob4.asp

Posted on: 10/25/2003

Science News

Week of Oct. 25, 2003; Vol. 164, No. 17

First Viruses, Now Tumors: AIDS drug shows promise against brain cancers

John Travis

An unlikely partnership between AIDS researchers seeking new antiviral therapies and developmental biologists exploring how the brain forms has produced a promising new drug for the fight against deadly brain tumors. In cell and animal studies, the drug, originally developed as an anti-HIV medication, has slowed the growth of several kinds of brain cancers.

"I hope and would like to think that this will end up being useful in human disease," says Rosalind A. Segal of the Dana-Farber Cancer Institute in Boston, who headed the work.

Several years ago, researchers discovered that for the AIDS virus to infect an immune cell, HIV must grab on to a cell-surface protein called a chemokine receptor. Chemokines are chemicals that guide immune cells around a body, and receptors allow the cells to detect the compounds.

When investigators created mice lacking the chemokine receptor CXCR4, which is one that HIV exploits, the rodents died as embryos, their hearts and blood vessels riddled with defects. The mutant animals also had malformed brains.

"What's become increasingly clear is that there's a deeper ancestral role for chemokines, particularly in patterning the nervous system," says Richard Ransohoff of the Cleveland Clinic.

Research groups led by Ransohoff, Segal, and several other scientists have discovered that CXCR4 and the chemokine that binds to it have multiple roles in a growing brain. The chemokine and its receptor keep brain cells alive and can stimulate their proliferation, for example.

Investigators have also found evidence that the cells of different brain tumors—from the occasionally treatable medulloblastomas to the almost-always-fatal glioblastomas—sport CXCR4 on their surface. The blood vessels that form to nourish a growing brain tumor apparently secrete the receptor's chemokine.

In an upcoming Proceedings of the National Academy of Sciences, Segal's group confirms the extensive presence of CXCR4 in various human brain cancers. Moreover, her team reports test tube studies showing that a drug that blocks this receptor slows the growth of medulloblastoma and glioblastoma cells. The researchers also implanted such cells in the brains of mice, permitted tumors to form, and treated the animals with injections of the drug, which is currently called AMD 3100. The drug "significantly decreased the growth of the tumors," says Segal.

AnorMED, a firm based in Langley, British Columbia, has already tested AMD 3100 in people as an AIDS drug and has seen few side effects. The company, along with Segal and her physician colleagues at Dana-Farber, are now discussing whether to try the compound on people with brain tumors that haven't responded to conventional therapies.

"Glioblastoma is a horrible disease with very little in the way of useful treatments. Therefore, the discovery of something that has even a spark of promise, with almost no downside, gives you a great deal of encouragement," says Ransohoff. "It would be crazy not to try it."

Segal notes that other kinds of cancers, such as kidney tumors, also appear to depend on the chemokine receptor CXCR4 and so might also be thwarted by drugs blocking it.

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References and Sources

References:

Rubin, J.B. . . . and R.A. Segal. In press. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proceedings of the National Academy of Sciences.

Further Readings:

Staller, P., et al. 2003. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425(Sept. 18):307-311. Abstract available at http://dx.doi.org/10.1038/nature01874.

Sources:

AnorMED, Inc. #200 - 20353 64th Avenue Langley, British Columbia V2Y 1N5 Canada

Richard M. Ransohoff
Department of Neurosciences
Lerner Research Institute / NC30
9500 Euclid Avenue
Cleveland, OH 44195


Rosalind A. Segal
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115


http://www.sciencenews.org/20031025/fob4.asp
From Science News, Vol. 164, No. 17, Oct. 25, 2003, p. 260.



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