Brain capillary endothelium and its contiguous cells, pericytes and astrocytes, are the structural and functional components of the blood-brain barrier (BBB). Microvessels supplying brain tumors retain characteristics of the BBB, forming a blood-tumor barrier (BTB). While adequate delivery of drugs occurs to systemic tumors, the BTB limits delivery of antineoplastic agents to metastatic brain tumors. Drugs such as Herceptin, which is effective in treating metastatic tumors outside the brain have a high failure rate within the brain due to inadequate delivery across the BTB. The incidence of metastatic brain tumors is ten-fold higher than primary brain tumors. We have demonstrated that calcium-sensitive potassium (KCa) channel agonists selectively increase drug delivery across the BTB, and have postulated the biochemical mechanisms of this selective BTB permeability increase. We also have preliminary data suggesting that ATP-sensitive potassium (KATP) channel agonists selectively increase BTB permeability independent of KCa channels. These novel observations allow for a pharmacological mechanism for selectively increasing drug delivery across the BTB. This proposal will (a) further understand the mechanisms of KCa, and KATP channel activation in increasing BTB permeability and (b) optimize delivery of effective concentrations of drugs to metastatic breast and lung tumors in rats and humans via potassium channel-based mechanisms. We build on our data showing the ability of KCa channel agonists to selectively increase drug delivery across the BTB in rat glioma models and preliminary evidence suggesting that the BTB permeability increase may relate to over expression of KCa channels on glioma cells and tumor capillary endothelium. In this grant we will investigate 5 specific aims.
Aim 1 : To determine whether KCa and KATP channels are over expressed in metastatic brain tumor microvessels and tumor cells and whether increased expression correlates with increased permeability induced by KCa and KATP agonists. To test whether tumor cells can induce over expression of KCa or KATP channels on brain endothelial cells.
Aim 2 : To test by quantitative electron microscopy whether the mechanism of KATP channel agonist-induced BTB permeability increase is due to increased endothelial vesicular transport or opening of tight junctions. To test whether increased vesicle formation is correlated with changes in endothelial and tumor cell membrane potential.
Aim 3 : To investigate whether KCa and KATP channel agonists increase delivery of therapeutic monoclonal antibodies and chemotherapeutic drugs across the BTB into metastatic human breast and lung cancer in nude rats/mice.
Aim 4 : In nude rats/mice harboring metastatic breast and lung tumors we will investigate whether increased drug delivery across the BTB using KCa or KATP agonists results in inhibition of tumor growth, and whether survival is increased.
Aim 5 : The ability of a KATP channel agonist, minoxidil, to increase delivery of an anti-tumor drug to patients with brain tumors will be determined by LC-MS-MS in resected tumor tissues. This grant is responsive to the recent Brain Tumor PRG recommendation in 2001 to support studies to improve delivery of drugs across the BBB, particularly for metastatic brain tumors. Overall, these studies will further delineate the role of KCa and KATP channel activation as a mechanism for selective delivery of anti-cancer agents across the BTB and could potentially result in improved control of disease in patients with metastatic brain tumors. ? ?
| Black, Keith L; Yin, Dali; Ong, John M et al. (2008) PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res 1230:290-302 |
| Black, Keith L; Yin, Dali; Konda, Bindu M et al. (2008) Different effects of KCa and KATP agonists on brain tumor permeability between syngeneic and allogeneic rat models. Brain Res 1227:198-206 |
| Ningaraj, Nagendra S; Rao, Mamatha K; Black, Keith L (2003) Adenosine 5'-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumor model. Cancer Res 63:8899-911 |
