| Because tumors require angiogenesis for growth and metastasis, inhibiting angiogenesis is a promising strategy for cancer treatment. The significant target genes for the treatment of solid tumors are not available at present, therefore the foundation of therapeutic strategies are mostly focused. Although numerous endogenous angiogenesis inhibitors have been discovered, the clinical evaluation of these agents has been hindered by high dose requirements, manufacturing constraints, and relative instability of the corresponding recombinant proteins. Tumors growth beyond a few millimeters and metastasis are dependent on the induction of angiogenesis mediated by the release of angiogenic factors secreted by the tumor cell. Vascular endothelial growth factor (VEGF) is among the major factors mediating tumor angiogenesis. Diphtheria toxin (DT) isa cytotoxic protein, secreted from P Corynebacteriophage diphtheriae. In this study, we constructed DT/VEGF chimeric genes to target activated endotheliai cells and VEGF-expressed tumor cells, which will be meaningful in the ribosyiating toxin gene therapy and anti?neovascularization gene therapy for gastric tumor. It has been demonstrated that angiogenesis was essential for the growth of solid tumors and their metastases. The growth of solid tumors beyond the size of 2.0mm3 is dependent on neovascularization. Angiogenesis is regulated by a balance between angiogenic factors and inhibitors, which bind to specific receptors on target cells. Endotheiial cells are activated by a number of tumor-derived growth factors, such as VEGF, fibroblast growth factors, platelet-derived endotheliai cell growth factor and so on. The high level expression of these growth factors will induce the rapid proliferation and metastases of tumors. VEGF is highly expressed in various types of tumors, but not in normal tissue. Anti-angiogenic therapy to limit and even reverse the growth of tumors is under investigation and shows promising. During vascuiarization, the blood vessels have special expression products, such as high level of α,β,integrin, oncofital fibronectin, KDR and Fit-1. VEGF receptors are expressed most ~: ~ 7 abundantly in the tumor vasculature and less abundantly in the endothelium of resting blood vessels. High levels of VEGFR expression in the tumor vasculature thus provide a unique opportunity for tumor targeting with agents that kill cells. Previous studies have found that oncogenic transformation with activated forms of the Src, Ras, and Raf? oncogenes could increase the expression of VEGF, and the p53 tumor suppressor gene could decrease the expression of VEGF, suggesting a link between tumorigenesis and angiogenesis. Acquired drug resistance is a major problem in the treatment of cancer. The emergence of resistance depends in part on the genetic instability, heterogeneity and high mutative rate of tumor cells. In contrast, endothelial cells are genetically stable, homogeneous and have a low mutative rate. Therefore, antiangiogenic therapy against a tumor抯 endothelial cells should, in principle, induce little or no drug resistance. This made VEGF become the target for the gene therapy. We have chosen DT for fusion with VEGF. DT is secreted as a mature protein of 535 amino acid residues with a Mr of 58,342. It can be cleaved into two fragments, DTA fragment (residues 1?93) and DTB fragment (residues 194?35), by the action of proteolytic...
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