PURPOSE: Tumor endothelial cells express vascular endothelial growth factor receptor 2 (VEGFR-2). VEGF can direct toxins to tumor vessels through VEGFR-2 for antiangiogenic therapy. This study aimed to selectively damage the VEGFR-2-overexpressing vasculature of pancreatic cancer by SLT-VEGF fusion protein comprising VEGF and the A subunit of Shiga-like toxin which inhibits protein synthesis of cells with high VEGFR-2 expression. EXPERIMENTAL DESIGN: Expression of VEGF and VEGF receptors was evaluated in human pancreatic cancer cells (AsPC-1, HPAF-2) and in normal human endothelial cells (HUVEC) by reverse transcription-polymerase chain reaction. Cells were treated with SLT-VEGF (0.1-10 nM), and cell viability, proliferation, and endothelial tube formation were assessed. Orthotopic pancreatic cancer (AsPC-1, HPAF-2) was induced in nude mice. Animals were treated with SLT-VEGF fusion protein alone or in combination with gemcitabine. Treatment began 3 days or 6 weeks after tumor induction. Primary tumor volume and dissemination were determined after 14 weeks. Microvessel density and expression of VEGF and VEGF receptors were analyzed by immunohistochemistry. RESULTS: SLT-VEGF did not influence proliferation of pancreatic cancer cells; HUVECs (low-level VEGFR-2) reduced their proliferation rate and tube formation but not their viability. SLT-VEGF fusion protein reduced tumor growth and dissemination, increasing 14-week survival (AsPC-1, up to 75%; HPAF-2, up to 83%). Results of gemcitabine were comparable with SLT-VEGF monotherapy. Combination partly increased the therapeutic effects in comparison to the respective monotherapies. Microvessel density was reduced in all groups. Intratumoral VEGFR-2 expression was found in endothelial but not in tumor cells. CONCLUSIONS: SLT-VEGF is toxic for tumor vasculature rather than for normal endothelial or pancreatic cancer cells. SLT-VEGF treatment in combination with gemcitabine may provide a novel approach for pancreatic cancer.
PURPOSE:Tumor endothelial cells express vascular endothelial growth factor receptor 2 (VEGFR-2). VEGF can direct toxins to tumor vessels through VEGFR-2 for antiangiogenic therapy. This study aimed to selectively damage the VEGFR-2-overexpressing vasculature of pancreatic cancer by SLT-VEGF fusion protein comprising VEGF and the A subunit of Shiga-like toxin which inhibits protein synthesis of cells with high VEGFR-2 expression. EXPERIMENTAL DESIGN: Expression of VEGF and VEGF receptors was evaluated in humanpancreatic cancer cells (AsPC-1, HPAF-2) and in normal human endothelial cells (HUVEC) by reverse transcription-polymerase chain reaction. Cells were treated with SLT-VEGF (0.1-10 nM), and cell viability, proliferation, and endothelial tube formation were assessed. Orthotopic pancreatic cancer (AsPC-1, HPAF-2) was induced in nude mice. Animals were treated with SLT-VEGF fusion protein alone or in combination with gemcitabine. Treatment began 3 days or 6 weeks after tumor induction. Primary tumor volume and dissemination were determined after 14 weeks. Microvessel density and expression of VEGF and VEGF receptors were analyzed by immunohistochemistry. RESULTS: SLT-VEGF did not influence proliferation of pancreatic cancer cells; HUVECs (low-level VEGFR-2) reduced their proliferation rate and tube formation but not their viability. SLT-VEGF fusion protein reduced tumor growth and dissemination, increasing 14-week survival (AsPC-1, up to 75%; HPAF-2, up to 83%). Results of gemcitabine were comparable with SLT-VEGF monotherapy. Combination partly increased the therapeutic effects in comparison to the respective monotherapies. Microvessel density was reduced in all groups. Intratumoral VEGFR-2 expression was found in endothelial but not in tumor cells. CONCLUSIONS: SLT-VEGF is toxic for tumor vasculature rather than for normal endothelial or pancreatic cancer cells. SLT-VEGF treatment in combination with gemcitabine may provide a novel approach for pancreatic cancer.
Authors: S R Wedge; D J Ogilvie; M Dukes; J Kendrew; J O Curwen; L F Hennequin; A P Thomas; E S Stokes; B Curry; G H Richmond; P F Wadsworth Journal: Cancer Res Date: 2000-02-15 Impact factor: 12.701
Authors: H Gitay-Goren; T Cohen; S Tessler; S Soker; S Gengrinovitch; P Rockwell; M Klagsbrun; B Z Levi; G Neufeld Journal: J Biol Chem Date: 1996-03-08 Impact factor: 5.157
Authors: Khalid A Mohamedali; Zhi Gang Li; Michael W Starbuck; Xinhai Wan; Jun Yang; Sehoon Kim; Wendy Zhang; Michael G Rosenblum; Nora M Navone Journal: Clin Cancer Res Date: 2011-02-22 Impact factor: 12.531
Authors: Khalid A Mohamedali; Yu Cao; Lawrence H Cheung; Walter N Hittelman; Michael G Rosenblum Journal: Mol Cancer Ther Date: 2013-07-15 Impact factor: 6.261