The blood-brain barrier and oncology: new insights into function and modulation

The efficacy of chemotherapy for malignant primary or metastatic brain tumo urs is still poor. This is at least partly due to the presence of the blood -brain barrier (BBB). The functionality of the BBB can be explained by phys icochemical features and efflux pump mechanisms. An overview of the literat ure is presented with emphasis on oncology. The BBB consists of capillary endothelial cells that lack fenestrations and are connected together with continuous tight junctions, with a high electr ical resistance. Permeability of tight junctions can be increased in vitro by contraction of the cytoskeleton, caused by bradykinin agonists. Differen t efflux pumps are present in the BBB. Examples are P-glycoprotein (P-gp), organic anion transporters, (OAT) and multidrug-resistance-associated prote ins (MRP)(1 and 3). These pumps act as a multi-specific efflux pump for var ious chemotherapeutic drugs. Experiments have shown that P-gp can be inhibi ted by different non-chemotherapeutic substrates such as cyclosporin A. The functionality in vivo of P-gp can be measured with positron emission tomog raphy and [C-11]-verapamil or with single photon emission computer tomograp hy and Tc-99m-sestamibi, MRP1 and MRP3 act as organic anion transporters that in vitro act as efflux pumps for substances that are conjugated or co-transported with glutathion e and glucuronide, respectively. Methotrexate has been recently demonstrate d to be transported by MRP1 and MRP3. Results of studies which demonstrate the clinical relevance and applicabili ty of BBB modulators are eagerly awaited. (C) 2000 Harcourt Publishers Ltd.