Background: Brain 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. Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14 C-paclitaxel. The accumulation of tracers and 14 C-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. Results: The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) 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 (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 10 5 mL/s/g and 1.6 ± 1.4 × 10 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 14 C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT. Conclusions: Our data showed increased permeation of fluorescent tracers and 14 C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.
Bibliographical noteFunding Information:
We would like to acknowledge National Cancer Institute and the National Institute of General Medical Sciences of the National Institutes of Health for funding this project.
The design of the study, experimental work, collection, analysis, and interpretation of data and writing the manuscript were funded by a grant from National Cancer Institute (R01CA166067-01A1/ R01CA166067–05). Interpretation of data and writing of manuscript were also funded by National Institute of General Medical Sciences of the National Institutes of Health (CTSI Award: U54GM104942). Microscopy imaging and image analysis were funded by National Institute of General Medical Sciences of the National Institutes of Health (the CoBRE P30 GM103488). Funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
- Brain metastases
- Fluorescent microscopy