Thema: News: Activating ion channels increases drug delivery to bt.
News: Activating ion channels increases drug delivery to bt.
Katja[a]
03.09.2002 18:12:17
J Pharmacol Exp Ther 2002;301:838-851.
Activating ion channels increases drug delivery to brain tumors
Karla Gale
Reuters Health
June 25, 2002
NEW YORK (Reuters Health) - Researchers at Cedars Sinai Medical Center in Los Angeles have devised a method of increasing the permeability of the blood-brain tumor barrier to enhance the delivery of chemotherapeutic agents.
Calcium-activated potassium channels play a pivotal role in blood-brain tumor barrier (BTB) permeability regulation, Dr. Keith L. Black and associates report in The Journal of Pharmacology and Experimental Therapeutics for June. Using rats, they found for the first time that these channels are overexpressed in brain tumor endothelial cells compared with normal brain tissue.
The capillary dilator bradykinin can increase BTB permeability, but the effect is transient and variable, Dr. Black´s group notes. They developed a synthetic form of bradykinin, NS-1619, which elicits enhanced and sustained drug delivery to tumor tissue by directly activating the calcium-activated potassium channels when infused into the carotid artery.
In their experiments, NS-1619 did not significantly affect cerebral blood flow, pH, arterial oxygen or carbon dioxide levels, or mean arterial blood pressure. However, it did lead to increased delivery of tracer molecules directly into tumors.
"NS-1619 is one of a possible list of drugs that may go into clinical studies," Dr. Black told Reuters Health. Other vasodilators, including nitric oxide donors, soluble guanylate cyclase activators, and cGMP, were also shown to activate the potassium channels.
Transmission electron microscopy demonstrated that the potassium channel agonists increased the density of transcytotic vesicles in the cytoplasm of brain tumor capillary endothelial cells and in the tumor cells themselves.
"We currently believe that by activating the potassium channel, the vasodilators change the membrane potential in [the] endothelial cell, which triggers formation of vesicles in the endothelial cell and allows transport and release of drugs directly into brain tumor cells," Dr. Black explained.
He noted that he and his associates have successfully increased the intracellular concentration of several tracer molecules of varying molecular weight. Since submission of their report, the researchers have also demonstrated enhanced delivery of labeled carboplatin into brain tumors.
"We also observed overexpression of these ion channels in brain areas of ischemia," Dr. Black said, suggesting that ion channel activation may be useful for preventing brain damage in patients after stroke.
Activating ion channels increases drug delivery to brain tumors
Karla Gale
Reuters Health
June 25, 2002
NEW YORK (Reuters Health) - Researchers at Cedars Sinai Medical Center in Los Angeles have devised a method of increasing the permeability of the blood-brain tumor barrier to enhance the delivery of chemotherapeutic agents.
Calcium-activated potassium channels play a pivotal role in blood-brain tumor barrier (BTB) permeability regulation, Dr. Keith L. Black and associates report in The Journal of Pharmacology and Experimental Therapeutics for June. Using rats, they found for the first time that these channels are overexpressed in brain tumor endothelial cells compared with normal brain tissue.
The capillary dilator bradykinin can increase BTB permeability, but the effect is transient and variable, Dr. Black´s group notes. They developed a synthetic form of bradykinin, NS-1619, which elicits enhanced and sustained drug delivery to tumor tissue by directly activating the calcium-activated potassium channels when infused into the carotid artery.
In their experiments, NS-1619 did not significantly affect cerebral blood flow, pH, arterial oxygen or carbon dioxide levels, or mean arterial blood pressure. However, it did lead to increased delivery of tracer molecules directly into tumors.
"NS-1619 is one of a possible list of drugs that may go into clinical studies," Dr. Black told Reuters Health. Other vasodilators, including nitric oxide donors, soluble guanylate cyclase activators, and cGMP, were also shown to activate the potassium channels.
Transmission electron microscopy demonstrated that the potassium channel agonists increased the density of transcytotic vesicles in the cytoplasm of brain tumor capillary endothelial cells and in the tumor cells themselves.
"We currently believe that by activating the potassium channel, the vasodilators change the membrane potential in [the] endothelial cell, which triggers formation of vesicles in the endothelial cell and allows transport and release of drugs directly into brain tumor cells," Dr. Black explained.
He noted that he and his associates have successfully increased the intracellular concentration of several tracer molecules of varying molecular weight. Since submission of their report, the researchers have also demonstrated enhanced delivery of labeled carboplatin into brain tumors.
"We also observed overexpression of these ion channels in brain areas of ischemia," Dr. Black said, suggesting that ion channel activation may be useful for preventing brain damage in patients after stroke.
Katja[a]
