A novel vascular endothelial growth factor-directed therapy that selectively activates cytotoxic prodrugs

Neoangiogenesis is critical for the growth, malignant progression, and metastatic spread of solid tumours and is effected by the release of angiogenic factors that are secreted by tumour cells (Fidler and Ellis, 1994; Folkman, 1995; Fukumura et al, 1998). One such angiogenic factor is vascular endothelial growth factor (VEGF) (Tischer et al, 1989). VEGF homodimers act by binding to two cell surface receptors (VEGFRs), known variously as VEGFR-1, flt-1, or fms-like tyrosine kinase, and VEGFR2, KDR, kinase insert domain-containing receptor, or flk-1. Alternate splicing of the VEGF transcript results in the expression of five isoforms of VEGF, comprising molecules consisting of 208, 189, 165, 145, or 121 amino acids (Leung et al, 1989; Tischer et al, 1989; Houck et al, 1991; Poltorak et al, 1997). Of these, only the three smallest variants, VEGF165, VEGF145, and VEGF121, are secreted as soluble factors. Cell-surface-associated heparin-like molecules enhance the binding of VEGF to its receptors. Of the three soluble variants, VEGF165 and VEGF145 contain such heparin-binding domains whereas VEGF121 does not.