Progress in antiangiogenic gene therapy of cancer

Abstract

Because tumors require angiogenesis for growth, inhibiting angiogenesis is a promising strategy for treating cancer patients. 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. Therefore the delivery of these proteins using gene therapy has become increasingly attractive. Based on their own antiangiogenic gene therapy research, the authors evaluated the published experience with antiangiogenic gene therapy models using the National Library of Medicine's PubMed search service and the reference lists of the publications cited. Greater than 40 endogenous inhibitors of angiogenesis have been characterized. Thirteen have been employed in gene therapy models, all of which showed antitumor activity in experimental animals. Other approaches have inhibited the expression or activity of proangiogenic cytokines such as vascular endothelial growth factor. The ideal gene delivery vector would target tumor tissue preferentially to minimize systemic toxicity of the transgene product. However, the low toxicity profile of endogenous inhibitors of angiogenesis has allowed the success of systemic antiangiogenic gene therapy in a number of preclinical models, in which normal host tissues act as a "factory" to produce high circulating concentrations of antiangiogenic proteins. Difficulties with the large-scale use of antiangiogenic agents have hindered their investigation in clinical trials. Antiangiogenic gene therapy offers the potential for cancer patients to manufacture their own antiangiogenic proteins. This strategy has been increasingly successful in preclinical models and represents an exciting new approach to cancer therapy.