Drugs that thwart the effect of a chemical secreted by certain cancerous brain cells could slow the growth of deadly brain tumors, a new study suggests.
The chemical, an amino acid called glutamate, normally acts as a neurotransmitter that brain cells use to signal each other. To serve this purpose, glutamate must move cleanly between cells. However, excess glutamate spilled into the space between cells can cause neurons, the information-carrying brain cells, to fire out of control and die.
In a healthy person, any excess glutamate is promptly gobbled up by glial cells, which are brain cells that support neurons. But in many glial-cell cancers, or gliomas, the tumor cells instead secrete glutamate. The resulting abundance of the neurotransmitter appears to kill neurons and create room for the cancerous glial cells to grow in the limited space within the skull. Moreover, glutamate secreted by glioma cells may cause surviving neurons to misfire and initiate epileptic seizures.
Scientists in Europe reported earlier this year that glutamate enhances the growth of various cancerous cell lines in lab dishes, whereas glutamate blockers thwart such growth. Wojciech Rzeski of Humboldt University in Berlin and his colleagues reported these findings in the May 22 Proceedings of the National Academy of Sciences.
In the September Nature Medicine, New York scientists now report that two compounds that impede excess glutamate's effect on neurons can salvage some of these cells in rats. In so doing, the drugs inhibit glioma's spread.
The researchers examined brains of rats with gliomas that naturally did or didn't secrete excess glutamate. Tumors releasing abundant glutamate were significantly larger than the rest, says study coauthor Takahiro Takano, a neuroscientist at New York Medical College in Valhalla.
Takano and his colleagues also found that two chemicals–dubbed MK801 and memantine–slow the growth of some glioma cells in lab dishes. When the researchers injected the compounds into rats with glutamate-releasing gliomas, both slowed tumor growth.
The study "provides compelling evidence that [glutamate] gives the tumor cells a growth advantage," says Harald Sontheimer, a neurobiologist at the University of Alabama in Birmingham.
How some tumor cells produce excess glutamate is unclear, Takano says. In healthy people, glial cells draw small amounts of glutamate from the blood and pass it to neurons for its controlled use as a neurotransmitter.
Besides destroying neurons, glioma cells engender inflammation. This attracts the brain's housekeeping cells, which haul away remains of the dead neurons, Takano says. Inflammation may also spur angiogenesis–the process of building new blood vessels–which nourishes a growing tumor, he says.
MK801 and memantine work by binding to receptor molecules on the surface of neurons. This leaves fewer docking sites for glutamate, which prevents it from overstimulating the cells, Sontheimer says. With no place to grow and little angiogenesis, the tumor is stifled.
However, occupying a receptor on neurons can keep them from firing normally and thus may disrupt brain function. Memantine seems to block receptors enough to ward off excess glutamate but still permits neurons to function, Takano says. Already prescribed in Europe for some brain disorders, it shows few side effects. But MK801 occupies more glutamate receptors, preventing the neurons from firing, and would be too strong for use in people, Takano suggests.
These and other recent studies "open up an entirely new treatment approach to fatal central nervous system tumors," Jeffrey D. Rothstein and Henry Brem of Johns Hopkins University Medical Institutions in Baltimore say in the September Nature Medicine.
Departments of Neurological Surgery and Oncology
Johns Hopkins University
Baltimore, MD 21218
Jeffery D. Rothstein
Department of Neurology
Johns Hopkins University
Baltimore, MD 21218
Department of Pediatric Neurology
Augustenburger Platz 1
University of Alabama-Birmingham
1719 Sixth Avenue South
Birmingham, AL 35294
Department of Cell Biology and Anatomy
Basic Science Building
New York Medical College
Valhalla, NY 10595
Ye, Z.C., J.D. Rothstein, and H. Sontheimer. 1999. Compromised glutamate transport in human glioma cells: Reduction-microlocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. Journal of Neuroscience 19:10767.
Ye, Z.C., and H. Sontheimer. 1999. Glioma cells release excitotoxic concentrations of glutamate. Cancer Research 59:4383.