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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

The MVD and the amount of vascular co-option, sprouting angiogenesis and IMG were obviously decreased on the 3rd day after treatment in the tumor region. indicating the variation in sprouting angiogenesis during drug treatment for GBM. Introduction Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite advances in tumor therapy, such as maximum surgical resection followed by radio-/chemo-therapy and immune/gene therapy1, Araloside V the prognosis of GBM patients is still poor, consisting of a median survival time of 14.6 months and a five-year survival rate lower Araloside V than 10%2,3. GBM is characterized by abundant and abnormal neovascularization, including vascular co-option, angiogenesis, vasculogenesis, Araloside V mosaic vessel formation, vascular mimicry, and glioblastoma-endothelial cell transdifferentiation4C7. Additionally, the neoplastic microvessels are leaky, endothelial cells are aberrant, and the pericytes and basement membrane are absent8 leading to a hypoxic and acidic microenvironment, which is closely related to tumor progression, metastasis and relapse9,10. As a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), bevacizumab (BEV) can block VEGF signal transduction to generate an anti-tumor effect by inhibiting neovascularization and suppressing edema11,12, but Rabbit Polyclonal to ALX3 as a result, BEV can also increase tumor cell invasion in GBM13. Temozolomide (TMZ) is an alkylating agent that promotes apoptosis and is used as a first-line chemotherapeutic agent against newly diagnosed GBM14. The use of TMZ could improve treatment for GBM2. However, resistance to TMZ impairs its therapeutic effect, and the mechanisms of TMZ resistance are still not clearly understood. Meanwhile, TMZ has been reported to inhibit tumor angiogenesis15. However, it is not clear which types of neovascularization patterns are sensitive to TMZ and BEV treatment. Pre-clinical studies are an important approach to explore tumor neovascularization patterns. For example, vascular co-option has been demonstrated in a rat C6 glioma model16. Vasculogenesis has been further demonstrated in the angiogenic, defective tumor resistant Id-mutant mouse model17. Glioblastoma-endothelial cell transdifferentiation has been shown in orthotopic GBM mice models18. Using orthotopic rat C6 glioma models, our group discovered a new mosaic pattern of glioma vascularization5 and confirmed vascular co-option, sprouting angiogenesis, intussusceptive microvascular growth (IMG) and vascular mimicry in the tumor region. We also demonstrated that neovascularization patterns varied along with tumor development and that dynamic contrast-enhanced MRI (DCE-MRI) can be used to evaluate neovascularization patterns in a glioma model19. Vascular parameters can be dynamically evaluated by MRI em in vivo /em . Dynamic susceptibility contrast MRI (DSC-MRI) can assess tumor vessel perfusion, and DCE-MRI can be used to evaluate vascular permeability20. DCE-MRI measures the MR signal to determine the change in concentration of the contrast agent over time within a field of view (FOV), and its quantitative parameters can be obtained through different pharmacokinetic models. For example, Ktrans reflects vessel permeability, Vp reflects plasma volume, and Kep reflects regurgitation of contrast media21. Ktrans has been reported to be strongly correlated with glioma vascular permeability and microvessel density (MVD) after anti-angiogenesis therapy22,23. Therefore, we used DCE-MRI to monitor the effect of anti-angiogenesis therapy in this study. Recently, many studies have demonstrated that different neovascularization patterns are mediated by corresponding signaling pathways24,25 with varying sensitivities to anti-angiogenic drugs26,27. However, few studies have examined the change in neovascularization patterns after treatment for GBM. In our study, orthotopic U87MG glioblastoma mouse models were administered TMZ, BEV or a combination of BEV and TMZ, and then DCE-MRI scanning and histopathological analysis were performed to investigate the changes in neovascularization patterns and MVD in the tumor region. We aimed to determine the relationship between neovascularization patterns and resistance to drug treatment and investigated MRI biomarkers that indicate changes in neovascularization patterns during treatment. Results MRI features and neovascularization patterns of a U87 GBM model GBM presented as a quasi-circular high signal in the right cerebral hemisphere in T2-weighted images. The signal was homogeneous, and mild edema was observed around the tumor mass. The Ktrans map derived from DCE-MRI showed high permeability in tumor tissues, especially at the tumor margin, indicated by bright.