Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer

BackgroundBrain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes.MethodsHuman metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28days, after which animals were injected fluorescent tracers Texas Red (625Da) or Texas Red dextran (3kDa) or a chemotherapeutic agent C-14-paclitaxel. The accumulation of tracers and C-14-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes.ResultsThe mean permeability of texas Red (625Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The K-in values in the BAT for both Texas Red (625Da) and Texas Red dextran (3kDa) were found to be 4.320.2x10(5)mL/s/g and 1.6 +/- 1.4x10(5)mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of C-14-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10mg/kg), erubilin (1.5mg/kg) and docetaxel (10mg/kg)) showed activated astrocytes in BAT.Conclusions p id=Par4 Our data showed increased permeation of fluorescent tracers and C-14-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.