The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma CellsIn vitroandIn vivo
Open accessAbstract
The cytokine transforming growth factor (TGF)-β, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas. Here we characterize the effects of a novel TGF-β receptor (TGF-βR) I kinase inhibitor, SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308 glioma cells in vitro and the growth of and immune response to intracranial SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth inhibition of TGF-β–sensitive CCL64 cells mediated by recombinant TGF-β1 or TGF-β2 or of TGF-β–containing glioma cell supernatant at an EC50 of 0.1 μmol/L. SD-208 blocks autocrine and paracrine TGF-β signaling in glioma cells as detected by the phosphorylation of Smad2 or TGF-β reporter assays and strongly inhibits constitutive and TGF-β–evoked migration and invasion, but not viability or proliferation. Peripheral blood lymphocytes or purified T cells, cocultured with TGF-β–releasing LN-308 glioma cells in the presence of SD-208, exhibit enhanced lytic activity against LN-308 targets. The release of interferon γ and tumor necrosis factor α by these immune effector cells is enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208 restores the lytic activity of polyclonal natural killer cells against glioma cells in the presence of recombinant TGF-β or of TGF-β–containing glioma cell supernatant. The oral bioavailability of SD-208 was verified by demonstrating the inhibition of TGF-β–induced Smad phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3 days after the implantation of SMA-560 cells into the brains of syngeneic VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic analysis revealed no difference in blood vessel formation, proliferation, or apoptosis. However, animals responding to SD-208 showed an increased tumor infiltration by natural killer cells, CD8 T cells, and macrophages. These data define TGF-β receptor I kinase inhibitors such as SD-208 as promising novel agents for the treatment of human malignant glioma and other conditions associated with pathological TGF-β activity.
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Metadata
- Authors
- Uhl, M., Aulwurm, S., Wischhusen, J., Weiler, M., Ma, J. Y., Almirez, R., Mangadu, R., Liu, Y.-W., Platten, M., Herrlinger, U., Murphy, A., Wong, D. H., Wick, W., Higgins, L. S., & Weller, M.
- Venue
- Cancer Research
- Published
- 2004-11-01
- Volume
- 64
- Issue
- 21
- Pages
- 7954-7961
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2110094917
- Cited by
- 414
- References
- 23
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Uhl, M., Aulwurm, S., Wischhusen, J., Weiler, M., Ma, J. Y., Almirez, R., Mangadu, R., Liu, Y.-W., Platten, M., Herrlinger, U., Murphy, A., Wong, D. H., Wick, W., Higgins, L. S., & Weller, M. (2004). SD-208, a Novel Transforming Growth Factor β Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma CellsIn vitroandIn vivo. Cancer Research. https://doi.org/10.1158/0008-5472.can-04-1013
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