| Mammalian cells require oxygen and nutrients for their survival and are therefore located within 100 to 200 u m of blood vessels - the diffusion limit for oxygen. For multicellular organisms to grow beyond this size, they must recruit new blood vessels by vasculogenesis and angiogenesis. This process is regulated by a balance between pro- and anti-angiogenic molecules, and is derailed in various diseases, especially tumor. Tumor angiogenesis is a process that tumor vessels develop by sprouting or intussusception from pre-existing vessels. Tumor vasculogenesis is a process that circulating endothelial precursors, mobilized from the bone marrow, contribute to tumor neovascularization. The ability of a tumor to become neovascularized permits rapid expansion of tumor growth and increases the likelihood of metastases.Cancer metastasis accounts for a significant proportion of mortality in patients. Effective means of treating disseminated disease remains elusive. Although there have been substantial advances in early detection and treatment of human cancers, survival for patients with certain forms of cancer has not improved. The prognosis for advanced tumors remains dismal, in part due to the occurrence of metastatic disease in many patients at the time of diagnosis and the ineffectiveness of currently available methods to treat metastatic disease. Consequently, novel treatment strategies are needed. Because the growth and metastasis of tumors are dependent on the formation of neo-vessels that arise in response to angiogenic factors elaborated by tumor cells themselves, in theoretically tumor anti-angjogenesis gene therapy appears to be a promising approach.In this regard, an important problem in the treatment of human tumors is posed by theneed to deliver therapeutic agents to tumors, distribute them and target them to primary tumors and/or disseminated metastatic foci. Both viral and nonviral vectors previously have been used clinically for the treatment of cancer, mostly in a loco-regional context. Among the vector systems that have been used successfully are viruses (retrovirus, adenovirus, and adeno-associated virus, poxviras, herpesvirus), naked DNA, and lipids. In general, despite their utility in selected applications, these vectors have been limited in their ability to accomplish highly efficient gene delivery to target cells in clinically relevant models. Furthermore, for disseminated cancer, vectors with consistent capacities for systemic gene delivery have not been available. Thus, shortcomings in the present generation of vectors have limited the overall efficacy and implementation of gene-based molecular chemotherapy for advanced cancer. As an alternative to these aforementioned vector approaches, cells have also been used as vectors. In this approach, cells are removed from the body, and therapeutic genes are transferred to the cells extracorporally, followed by their reimplantation back into the patient. In this manner, the genetically modified cell itself becomes the ultimate vector for gene delivery. Conceivably, a variety of genes can be introduced in candidate cellular vehicles, and expression of these payloads can be obtained in an environment where these cells localize. A loco-regional effect subsequent to the expression of the therapeutic gene can thus be achieved in areas otherwise inaccessible to direct gene transfer.Endothelial cells are excellent vehicles for drug delivery for tumor anti-angiogenesis therapy because of their ability to express a wide variety of endogenous and exogenous genes, and their strategic location within the vascular compartment. For delivery of therapeutic factors to tumors, gene transfer using implantation of engineered cells appears as an attractive approach. Such cell-based gene transfer requires harvesting endothelial cells, in vitro expansion and transduction followed by administration of the genetically modified cells, which are able to incorporated into endothelium of the microvascular network. However, primary endothelial cells have a limited life span... |
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