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- W2030018892 abstract "Ionizing radiation triggers activation of transforming growth factor β1 (TGFβ), a growth factor that promotes invasion and suppresses immune function. Either genetic or pharmaceutical TGFβ inhibition prior to IR also inhibits the DNA damage response (DDR) in epithelial cells via blockade of ATM kinase activity (Cancer Res 62:5627, 2002; Cancer Res 66:10861, 2006). Moreover, transient TGFβ inhibition increases the radiosensitivity of epithelial cancer cells (Bouquet et al. submitted). The current studies test the optimal combination of TGFβ inhibition using neutralizing antibodies with radiotherapy (RT) in a model of triple negative breast cancer. The 4T1 murine mammary tumor model is highly metastatic when grown as subcutaneous tumors. 4T1 cells were injected s.c. in the flank of syngeneic Balb/c mice and about 13 days after implantation approximately 100 mm3 tumors were locally irradiated. An anti-TGFβ murine monoclonal antibody, 1D11, was administered i.p. before irradiation. Mice were randomly assigned to four groups receiving control isotype monoclonal antibody, 1D11, RT (8 Gy) and isotype control antibody, or RT and 1D11. Tumor growth, DDR, lymphocyte infiltration, lung metastases and/or survival were evaluated. TGFβ TGFβ inhibition in vivo reduced DDR as evidenced by gH2AX foci in irradiated tumors. A single injection of 1D11 (5 mg/kg) 24 hr before RT resulted in greater tumor growth delay compared to RT and control antibody (p<0.05). Furthermore, chronic treatment with a higher 1D11 dose (10 mg/kg or 50 mg/kg) in the context of fractionated RT significantly reduced tumor growth rate, decreased visible lung metastases and increased survival (p<0.05). Notably this RT+1D11 protocol increased tumor infiltration of CD8, but not CD4, T lymphocytes, which resulted in a significantly enhanced ratio of CD8+NKG2D+ effector cells to CD4+ T cells in the tumor, suggesting that TGFβ inhibition also alters the immunological environment in irradiated tumors. Increased radiosensitivity of 4T1 tumor cells in vitro and in vivo supports the use of TGFβ inhibitors as means to increase the response to RT. Moreover, an additional benefit may be that TGFβ inhibition promotes an anti-tumor immune response to RT." @default.
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- W2030018892 date "2011-10-01" @default.
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- W2030018892 title "Increased Radiosensitivity In Vivo following Inhibition of Transforming Growth Factor Beta in Murine Model of Triple Negative Breast Cancer" @default.
- W2030018892 doi "https://doi.org/10.1016/j.ijrobp.2011.06.1269" @default.
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