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- W2016169640 abstract "Purpose/Objective: SU11248 is a novel, broad-spectrum tyrosine kinase inhibitor of VEGFR2, PDGFR, c-kit and FLT3 that targets tumor vasculature. The aim of our project was to determine the effectiveness of SU11248 in preventing murine tumor growth, alone or in combination with radiotherapy, as well as regrowth following completion of radiotherapy. Materials/Methods: The in vitro cytotoxicity of SU11248 was demonstrated in HUVEC cells both by clonogenic assay and by counting apoptotic nuclei (H&E) 24 hours following treatment. In vivo tumor control was demonstrated in C57B6J mice with either Lewis Lung Carcinoma (LLC) or Glioblastoma Multiforme (GL261) tumors. Effects of treatment on vascular length density were assessed in a dorsal vascular window model. Mice with LLC and GL261 hind limb tumors were treated with daily i.p. injections (40 mg/kg) of SU11248 during 7 days of radiation treatment (21 Gy), and serial volumetric measurements were obtained. SU11248 therapy was continued in select groups of mice following discontinuation of radiotherapy. Results: SU11248 significantly increased the reduction of apoptosis and significantly decreased clonogenic survival of endothelial cells treated with radiation. Concomitant reduction in vasculature was confirmed using the dorsal vascular window model. The vascular length established using images taken from a consistent quadrant in the window show the combination therapy was more effective in destroying tumor vasculature than either treatment alone. Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared to either treatment alone. SU11248 maintenance administration beyond the completion of radio-, chemo-, or combined therapy results in prolongation of tumor control. Waves of tumor regrowth and regression were achieved during interruption and reinstitution of therapy. This indicates that resistance to this vascular targeted therapy does not develop. Conclusions: SU11248 enhances radiation-induced endothelial cytotoxicity resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models; moreover, blocking angiogenesis well beyond radiation-induced hypoxic tumor insult may be a promising treatment paradigm for refractory human neoplasms including malignant gliomas and lung cancer. Work was supported by grants R21-CA89888, R01-CA70937, R01-CA58508, P30-CA68485, R01-CA88076, R01-CA89674, and Lung Cancer SPORE P50-CA90949." @default.
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- W2016169640 date "2003-10-01" @default.
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- W2016169640 title "Tyrosine kinase inhibition prevents tumor regrowth following fractionated irradiation of murine tumor models" @default.
- W2016169640 doi "https://doi.org/10.1016/s0360-3016(03)01156-8" @default.
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