Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer

Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growt h in different animal tumor models, the relative potency of those gene prod ucts has not been studied rigorously. To address this issue, recombinant ad enoviruses encoding angiostatin, endostatin, and the ligand-binding ectodom ains of the vascular endothelial growth factor receptors Flk1, Flt1, and ne uropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in a pproximate to 80% inhibition of preexisting tumor growth in murine models i nvolving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (B xPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angio statin, endostatin, or neuropilin were significantly less effective. A stro ng correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative an alyses of different therapeutic approaches that target tumor angiogenesis a nd provide a rationale for the selection of specific antiangiogenic gene pr oducts as lead candidates for use in gene therapy approaches aimed at the t reatment of malignant and ocular disorders.