Results of the study appear as the cover article of the June issue of the Journal of Pharmacology and Experimental Therapeutics. The findings represent what may be a major step toward providing significantly more effective drug therapy for patients suffering from brain tumors.
The blood-brain tumor barrier is a mechanism that naturally occurs within brain tumor capillaries, the tiny blood vessels at the ends of small arteries that feed a tumor. The BTB functions as a tumor’s defense mechanism, significantly blocking the amount of cancer-killing medications that reach the tumor.
The key to the blood-brain tumor barrier – and the researchers’ ability to manipulate it – is the activity that takes place within the cells of tumor capillaries at the calcium-dependent potassium channels.
Many functions of cells depend on positive- and negative-charged chemicals, or ions, flowing into and out of the cells through membranes. Ions enter and exit through protein structures called channels. Specific channels permit passage of specific ions, and gates open and close to regulate the flow. While some gates are controlled by voltage changes, others are “activated” by the presence of a secondary chemical, in this case, calcium.
Previous studies have shown that calcium-dependent potassium channels in cerebral blood vessels regulate vessel tone, affecting dilation and constriction. Another important function performed by calcium-dependent potassium channels is preventing toxins in the bloodstream from passing through the cells and reaching those of the brain. Ironically, the body’s natural defense to protect brain cells from chemical damage also blocks cancer-fighting drugs from reaching tumors.
Keith L. Black, M.D., director of Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute since it was founded in 1997, has led numerous studies over more than a decade to investigate this phenomenon. Prior to joining Cedars-Sinai, he and colleagues at the University of California, Los Angeles discovered that bradykinin, a natural body peptide, provided entry into tumors but not into the normal brain. By creating a synthetic version of bradykinin, they were able to make chemotherapy treatments up to 1,000 times more effective than before.
The new study is believed to be the first to describe the occurrence of calcium-dependent potassium channels in endothelial cells – those in the lining, or endothelium, of a vessel – in either normal or tumor-feeding capillaries in the brain. Scientists knew from previous research that the channels were found in endothelial cells of larger vessels, but this study documents their existence in the tiny capillaries and investigates their impact on capillary permeability.
The researchers found overexpression of calcium-dependent potassium channels in rat brain tumor cells and capillaries, compared to normal brain tissue. They administered into the carotid artery agents that activate calcium-dependent potassium channels and others that affect the dilation of vessels. Bypassing the normal cellular signaling mechanisms, they were able to directly activate the potassium channels.
This enabled them to increase blood-brain tumor barrier permeability and significantly increase the amount of a tracer going into tumors. Not only was the BTB effectively “opened,” the duration of these changes was longer and more consistent than was previously possible.
These results, according to the article, were caused by an increased formation of vesicles that carry fluid across cell structures. When bradykinin, a capillary dilator, and NS-1619, a chemical that opens calcium-dependent channels, were introduced, transcytotic vesicle formation was accelerated. These new vesicles rapidly carried the tracer, horseradish peroxide, across the BTB and into tumor cells.
By contributing to the understanding of mechanisms that regulate BTB permeability for selective and enhanced delivery of molecules across brain tumor microvessels, this study may have significant implications for improving the targeted delivery of anti-cancer drugs and other therapeutic agents.
The paper’s first author is research scientist Nagendra S. Ningaraj, Ph.D., and the study was conducted by physicians and scientists from the Maxine Dunitz Neurosurgical Institute and Burns and Allen Research Institute at Cedars-Sinai Medical Center, the Atherosclerosis Research Center, Division of Cardiology, at Cedars-Sinai, and the Confocal Microscopy Facility. The work was supported by National Institutes of Health grants NS32103, NS25554, RR13707, and the Javits Neuroscience Investigator Award to Keith L. Black, M.D.
The full published article is available online at http://jpet.aspetjournals.org/cgi/content/abstract/301/3/838?ijkey=SqBzpYq8z/43k.
Cedars-Sinai Medical Center is one of the largest non-profit academic medical centers in the Western United States. For the fifth straight two-year period, Cedars-Sinai has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 "Most Wired" hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.
Journal
Journal of Pharmacology and Experimental Therapeutics