Different effects of KCa and KATP agonists on brain tumor permeability between syngeneic and allogeneic rat models.
The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (K(ATP) agonist), minoxidil sulfate (K(ATP) agonist) or NS1619 (K(Ca) agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both K(ATP) and K(Ca) channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of K(ATP) in surgical specimens. K(ATP) mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of K(ATP) were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.
Black
Keith L
KL
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800 E., Los Angeles, California 90048, USA. keith.black@cshs.org
Yin
Dali
D
Konda
Bindu M
BM
Wang
Xiao
X
Hu
Jinwei
J
Ko
MinHee K
MK
Bayan
Jennifer-Ann
JA
Sacapano
Manuel R
MR
Espinoza
Andres J
AJ
Ong
John M
JM
Irvin
Dwain
D
Shu
Yan
Y
D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D054086:KATP Channels / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D018613:Microscopy, Confocal; D008914:Minoxidil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D014611:Vaccination / Q000379:methods
D001562:Benzimidazoles; D054086:KATP Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; C086491:NS 1619; C039516:minoxidil sulfate ester; D008914:Minoxidil