Approximately 555,500 people die from cancer in the United States each year. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry (see "Cancer Treatment 2002" for a full analysis of current and future pharmaceutical approaches to cancer). One molecular target that has received much attention with respect to anti-cancer therapeutics is vascular endothelial growth factor (VEGF).

Discovered in the 1980's, VEGF is one of the archetypal angiogenic growth factors and has received considerable attention. VEGF is a homodimeric 45kDa glycoprotein, 3 different isoforms of which are reportedly expressed by endothelial cells. The VEGF gene contains 8 exons which express a 189-amino acid isoform. A 165-amino acid isoform lacks the residues encoded by exon 6, whereas a 121-amino acid isoform lacks the residues encoded by exons 6 and 7. By RT-PCR on carcinoma cell lines, a further VEGF isoform predicted to contain 145 amino acids and to lack exon 7, has been identified and termed VEGF145. VEGF specifically acts on endothelial cells binding to a growing number of endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation and vasculogenesis. A third receptor, VEGFR-3 has been implicated in lymphogenesis.

The various isoforms have distinct biologic activities and clinical implications. For example, VEGF145 induces angiogenesis and like VEGF189, but unlike VEGF165, VEGF145 binds efficiently to the extracellular matrix by a mechanism that is not dependent on ECM-associated heparan sulfates. On the other hand the isoform-specific VEGF receptor, VEGF165R (human neuropilin-1) binds VEGF165 but not VEGF121 and may modulate VEGF binding to KDR and hence VEGF-induced angiogenesis.

Several strategies have been developed to block VEGF for cancer therapy; however, approaches that target specific VEGF isoform(s) have not been explored to date. Philadelphia-based researchers have recently addressed this issue through DNA vector-based RNA interference (RNAi) technology. This group led by George Coukos has demonstrated that large molecular weight VEGF isoforms can be specifically reduced in vitro in the presence of isoform-specific RNAi constructs.

Given the different isoforms and their various functions, the development of this RNAi technology and its ability to target specific VEGFs should facilitate both a greater understanding of this field and also the development of improved therapeutics.

Entry date Monday, May 19, 2003

Adapted from Zhang et al, Biochem Biophys Res Commun 2003 Apr 18;303(4):1169-78 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk