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lüll Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo Ge R; Rajeev V; Ray P; Lattime E; Rittling S; Medicherla S; Protter A; Murphy A; Chakravarty J; Dugar S; Schreiner G; Barnard N; Reiss MClin Cancer Res 2006[Jul]; 12 (14 Pt 1): 4315-30PURPOSE: Transforming growth factor-beta (TGF-beta) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-beta, they often constitutively overexpress and activate TGF-beta, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-beta pathway antagonists. EXPERIMENTAL DESIGN: We examined the effects of selective TGF-beta type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo. RESULTS: Both agents blocked TGF-beta-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-beta failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-beta. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis. CONCLUSION: TGF-beta type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.|*Gene Expression Regulation, Neoplastic[MESH]|Animals[MESH]|Antineoplastic Agents/*pharmacology[MESH]|Apoptosis[MESH]|Carcinoma/*drug therapy[MESH]|Cell Proliferation[MESH]|Disease Progression[MESH]|Epithelium/pathology[MESH]|Humans[MESH]|Inhibitory Concentration 50[MESH]|Mammary Neoplasms, Animal/*drug therapy[MESH]|Mesoderm/pathology[MESH]|Mice[MESH]|Mice, Nude[MESH]|Neoplasm Metastasis[MESH]|Plasminogen Activator Inhibitor 1/metabolism[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors[MESH]|Pteridines/pharmacology[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta[MESH] |