Article Figures & Data
Figures
- Figure 1.
Chemical structures. The structure of dasatinib and GF120918 are shown.
- Figure 2.
Oncogene-induced glioblastoma model. A, schematic illustrating transposon vectors delivered into neonatal mice to initiate glioblastoma. Tumors were tractable by bioluminescent imaging as illustrated by a representative animal imaged longitudinally. B, representative histologic features of the tumor from a moribund animal by H&E staining. Black box in low-power sagittal image shows corresponding region highlighted at higher power. Top panel, document infiltrative growth pattern. Arrows in lower left panel highlight areas of necrosis. Lower right panels are examples of microvascular proliferation.
- Figure 3.
BBB permeability in the tumor visualized by Texas red dextran. A, 4 WT tumor-bearing mice were systemically injected with TRD. Representative qualitative images show higher TRD accumulation in the tumor relative to the adjacent normal brain. B, the concentration of TRD is approximately 3.6-fold higher in the tumor region compared with normal brain. Each symbol represents a measurement; 5 to 6 measurements were made per brain in 4 total animals (***, P < 0.0001).
- Figure 4.
Comparison of dasatinib brain distribution in WT and KO mice. A, and B, the plasma and brain concentrations of dasatinib, respectively, after 15 mg/kg oral dose. The brain-to-plasma ratio for dasatinib in WT and KO mice is shown in C. Data represent mean ± SD; n = 3–4 for all data points (*, P < 0.05, **, P < 0.01, ***, P ≤ 0.001).
- Figure 5.
Regional differences in dasatinib concentration and signal transduction. A, representative example illustrating how the brain tissue was dissected using GFP goggles. The brain was sliced in half coronally to expose the tumor expressing GFP. The center was considered the core, the tissue immediately adjacent to center was considered the rim, and the opposite hemisphere was considered normal brain. B, brain concentration of dasatinib in each region of brain tissue was quantified. Each symbol represents a measurement from an individual animal (n = 9 WT, n = 5 KO; *, P < 0.05, **, P < 0.01). C, Western blot analysis of brain tissue from WT and KO mice. Representative blots from 3 to 4 WT and 3–4 KO total mice are shown. Each panel represents a pair of individual mice (1 WT, 1 KO) that were analyzed side-by-side on the same gel.
- Figure 6.
Enhanced efficacy of dasatinib in BCRP/Pgp-deficient mice. Mice were enrolled into the indicated treatment arm as soon as tumors became apparent by bioluminescent imaging. Each group represents the cumulative survival of 5 to 8 individual mice that were treated at different times. The time scale indicates elapsed time from the day of enrollment. Significant differences in survival were determined by the log-rank test.
- Figure 7.
Inhibition of BCRP/Pgp sensitizes human glioma cells to dasatinib. A, the relative expression of BCRP and Pgp is shown by Western blot in 6 human GBM xenograft lines. The IC50 values in the presence of GF120918 is shown directly above the corresponding cell lines in the Western blot. B, representative cell survival curves of 4 of the cell lines shown in A.
Additional Files
Supplementary Data
Files in this Data Supplement:
- Supplementary Table 1 - PDF file, 71K, Pharmacokinetic Parameters in WT and TKO Mice after Oral Dosing with 15 mg/kg Dasatinib (Data presented as Mean � S.E. of Estimate).
Volume 11, Issue 10
