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  • Vascular normalization in orthotopic glioblastoma following intravenous treatment with lipid-based nanoparticulate formulations of irinotecan (Irinophore C™), doxorubicin ... 21477311

    Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion in the tumor. The present study evaluates how treatment with liposomal formulation of irinotecan (Irinophore C™), and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously.Liposomal vincristine (2 mg/kg), doxorubicin (Caelyx®; 15 mg/kg) and irinotecan (Irinophore C™; 25 mg/kg) were injected intravenously (i.v.; once weekly for 3 weeks) in Rag2M mice bearing U251MG tumors. Tumor blood vessel function was assessed using the marker Hoechst 33342 and by magnetic resonance imaging-measured changes in vascular permeability/flow (Ktrans). Changes in CD31 staining density, basement membrane integrity, pericyte coverage, blood vessel diameter were also assessed.The three liposomal drugs inhibited tumor growth significantly compared to untreated control (p less than 0.05-0.001). The effects on the tumor vasculature were determined 7 days following the last drug dose. There was a 2-3 fold increase in the delivery of Hoechst 33342 observed in subcutaneous tumors (p less than 0.001). In contrast there was a 5-10 fold lower level of Hoechst 33342 delivery in the orthotopic model (p less than 0.01), with the greatest effect observed following treatment with Irinophore C. Following treatment with Irinophore C, there was a significant reduction in Ktrans in the orthotopic tumors (p less than 0.05).The results are consistent with a partial restoration of the blood-brain barrier following treatment. Further, treatment with the selected liposomal drugs gave rise to blood vessels that were morphologically more mature and a vascular network that was more evenly distributed. Taken together the results suggest that treatment can lead to normalization of GBM blood vessel the structure and function. An in vitro assay designed to assess the effects of extended drug exposure on endothelial cells showed that selective cytotoxic activity against proliferating endothelial cells could explain the effects of liposomal formulations on the angiogenic tumor vasculature.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB5384

  • The histone demethylase JARID1A regulates progesterone receptor expression. 21348942

    Transcriptional control of the progesterone receptor gene by estrogen is a complex mechanism. It involves estrogen receptor α which uses several enzymes that locally modify histone tails as cofactors. Using MCF-7 cells as a model, we found that Jumonji AT-rich interactive domain 1A (JARID1A; KDM5A/RBP2), an enzyme that removes the activating H3K4 di- and trimethylation marks, was involved in the fine-tuning of progesterone receptor gene expression. Reduction of JARID1A led to enhanced progesterone receptor expression, at both the basal and estrogen-stimulated levels. Conversely, overexpression of JARID1A wild-type, but not the enzymatically inactive mutant, suppressed progesterone receptor promoter activity. Chromatin immunoprecipitation experiments showed JARID1A to bind in a ligand-independent manner to a progesterone receptor gene upstream region that contains an estrogen response element half-site as well as the CCGCCC sequence, which is potentially recognized by JARID1A. Estrogen treatment led to RNA polymerase II recruitment to this region and to increased estrogen receptor α binding to the PR enhancer region 1. In addition, elevation of H3K4 trimethylation was detected at the estrogen response element half-site region. Reduction of JARID1A expression was followed by higher H3K4 trimethylation in this region. Analysis of MDA-MB-231 cells, which do not express the progesterone receptor, indicated that H3K4 trimethylation did not take place in the regulatory regions examined. Taken together, the results underscore the importance of epigenetic modifications for regulation of progesterone receptor expression. They suggest that H3K4 tri- and dimethylation play an important role and that JARID1A is the histone-demethylating enzyme responsible for removal of this mark.
    Tipo de documento:
    Referencia
    Referencia del producto:
    PP64
    Nombre del producto:
    IgG, Rabbit
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