SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells In vitro and In vivo
作者： Martin Uhl , Steffen Aulwurm , Jörg Wischhusen , Markus Weiler , Jing Ying Ma
DOI: 10.1158/0008-5472.CAN-04-1013
关键词: Interleukin 10 、 Cytokine 、 Immune system 、 Biology 、 Cancer research 、 Glioma 、 Paracrine signalling 、 Autocrine signalling 、 Cytotoxic T cell 、 Interferon gamma
摘要: The cytokine transforming growth factor (TGF)-beta, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment human malignant gliomas. Here we characterize effects novel TGF-beta receptor (TGF-betaR) I kinase inhibitor, SD-208, on immunogenicity murine SMA-560 LN-308 glioma cells in vitro immune response to intracranial gliomas syngeneic VM/Dk mice vivo. SD-208 inhibits inhibition TGF-beta-sensitive CCL64 mediated recombinant TGF-beta1 or TGF-beta2 TGF-beta-containing cell supernatant at an EC(50) 0.1 mumol/L. blocks autocrine paracrine signaling as detected phosphorylation Smad2 reporter assays strongly constitutive TGF-beta-evoked migration invasion, but not viability proliferation. Peripheral blood lymphocytes purified T cells, cocultured with TGF-beta-releasing presence exhibit enhanced lytic activity against targets. release interferon gamma tumor necrosis alpha these effector is whereas interleukin 10 reduced. restores polyclonal natural killer supernatant. oral bioavailability was verified demonstrating TGF-beta-induced Smad spleen brain. Systemic initiated 3 days after implantation into brains prolongs their median survival from 18.6 25.1 days. Histologic analysis revealed no difference vessel formation, proliferation, apoptosis. However, animals responding showed increased infiltration CD8 macrophages. These data define inhibitors such promising agents other conditions associated pathological activity.
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