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 KCa 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 C nineteen patients examined, with a wide range of expression levels. interestingly, in paired GM 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. (C) 2008 Elsevier B.V. All rights reserved.