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      VEGF 165b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy

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          Abstract

          Bevacizumab, an anti-vascular endothelial growth factor (VEGF-A) antibody, is used in metastatic colorectal carcinoma (CRC) treatment, but responses are unpredictable. Vascular endothelial growth factor is alternatively spliced to form proangiogenic VEGF 165 and antiangiogenic VEGF 165b. Using isoform-specific enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, we found that over 90% of the VEGF in normal colonic tissue was VEGF xxxb, but there was a variable upregulation of VEGF xxx and downregulation of VEGF xxxb in paired human CRC samples. Furthermore, cultured colonic adenoma cells expressed predominantly VEGF xxxb, whereas colonic carcinoma cells expressed predominantly VEGF xxx. However, adenoma cells exposed to hypoxia switched their expression from predominantly VEGF xxxb to predominantly VEGF xxx. VEGF 165b overexpression in LS174t colon cancer cells inhibited colon carcinoma growth in mouse xenograft models. Western blotting and surface plasmon resonance showed that VEGF 165b bound to bevacizumab with similar affinity as VEGF 165. However, although bevacizumab effectively inhibited the rapid growth of colon carcinomas expressing VEGF 165, it did not affect the slower growth of tumours from colonic carcinoma cells expressing VEGF 165b. Both bevacizumab and anti-VEGF 165b-specific antibodies were cytotoxic to colonic epithelial cells, but less so to colonic carcinoma cells. These results show that the balance of antiangiogenic to proangiogenic isoforms switches to a variable extent in CRC, regulates tumour growth rates and affects the sensitivity of tumours to bevacizumab by competitive binding. Together with the identification of an autocrine cytoprotective role for VEGF 165b in colonic epithelial cells, these results indicate that bevacizumab treatment of human CRC may depend upon this balance of VEGF isoforms.

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
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              A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.

              Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P 0.20 for all comparisons). Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                18 March 2008
                15 April 2008
                22 April 2008
                : 98
                : 8
                : 1366-1379
                Affiliations
                [1 ]Microvascular Research Laboratories, Department of Physiology and Pharmacology, School of Veterinary Sciences, University of Bristol Bristol, UK
                [2 ]Department of Surgery, Frenchay Hospital Bristol, UK
                [3 ]Department of Cellular and Molecular Medicine, University of Bristol Bristol, UK
                Author notes
                [* ]Author for correspondence: dave.bates@ 123456bris.ac.uk
                Article
                6604308
                10.1038/sj.bjc.6604308
                2361696
                18349829
                57445652-0142-4aa6-8aa2-db1727c21d23
                Copyright 2008, Cancer Research UK
                History
                : 31 January 2008
                : 20 February 2008
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy
                biomarker,bevacizumab,colon carcinoma,vegf,vegf165b,angiogenesis
                Oncology & Radiotherapy
                biomarker, bevacizumab, colon carcinoma, vegf, vegf165b, angiogenesis

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