Experimental Study Of Vegf-targeting Antisense Gene Therapy Of Leukemia

Vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vasculogenesis, is involved in a variety of physiological and pathological processes. The VEGF belongs to a gene family that includes placenta growth factor (PLGF), VEGF-B, VEGF-C, VEGF-D, in which VEGF has been under most intense investigation. Alternative exon splicing results in the generation of four different isoforms: VEGF121, VEGF165, VEGF189 and VEGF206, in which VEGF121 and VEGF165 have potent biological activities. VEGF121, which lacks the residues encoded by exon 7 responsible for heparin binding, is the most soluble isoform. VEGF is a pleiotropic growth factor with multiple biological activities, which are mediated by VEGF binding with high affinity to two tyrosine kinase receptors VEGFR-1 and VEGFR-2. Because high affinity VEGF-binding receptors frequently were found to be expressed on the vascular endothelium, most effects of VEGF are thought to be restricted to endothelial cells (EC), such as EC survival, proliferation, migration, formation of tube structures of EC, and vessel permeability and vasodilation. Extensive studies have demonstrated that the growth and metastasis of solid tumors are dependent on VEGF-induced angiogenesis. In the other hand, over-expression of VEGF in ischemic tissue can induce neo-vessels formation, and restore the blood supply.Recent studies have further showed that a variety of human malignancies, including leukemia, had increased microvessel density in bone marrow, suggesting that angiogenesis plays a role not only in solid tumor but also in hematologic malignancies development and progression. Correspondingly, the elevated level of cellular or circulation VEGF was found to be associated with increased angiogenesis in patients with hematologic malignancies. The expression of VEGF was also found in almost all hematopoietic cell lines, but...