ABSTRACT
BACKGROUND: In this review we provide the reader with an analysis of the importance of VEGF in modulating the angiogenic process in vascular diseases. OBJECTIVES: We have described the key role of VEGF in the development of the major angiogenic diseases including ocular retinopathies, solid tumour growth and atherosclerotic plaque development. METHODS: Following a brief description of the disease, a detailed literature review of the mechanisms through which VEGF induces promotion of neovascularisation and current anti-VEGF therapies is provided for the reader. RESULTS/CONCLUSIONS: Current and future potential clinical therapies are discussed in particular concerning our thoughts on future directives involving adenoviral-mediated gene targeting, nanotechnology and combinational therapies.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Vascular Endothelial Growth Factors/antagonists & inhibitors , Angiogenesis Inhibitors/chemistry , Animals , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Eye Diseases/drug therapy , Eye Diseases/metabolism , Humans , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/metabolism , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factors/metabolismABSTRACT
The developmental gene PAX 3 is expressed in the early embryo in developing muscle and elements of the nervous system, including the brain. Since no one has investigated the expression of the isoforms of PAX 3 in the neuroectodermal tumors melanoma and small cell lung cancer (SCLC), we have carried out a comprehensive screening for the expression of the isoforms PAX 3a-e using RT-PCR in human melanoma cell lines, primary human ocular and secondary cutaneous melanomas. We have identified 2 new isoforms of PAX 3, g and h, which we have isolated, cloned and sequenced. Sets of primers for each isoform were designed and their specificity was confirmed by sequence analysis of the products. The isoforms PAX 3a-e were detected in all human cutaneous melanoma cell lines (8/8), but only PAX 3c (1/2) and PAX 3d (2/2) in ocular melanoma cell lines. The same PAX 3 isoforms were detected in more than 80% of human cutaneous melanomas: PAX 3a and b (15/17), PAX 3c (14/17), PAX 3d (16/17) and PAX 3e (15/17). In contrast the results for 7 SCLC cell lines were PAX 3a (0/7), PAX 3b (1/7), PAX 3c (3/7), PAX 3d (6/7), PAX 3e (2/7); 8/8 cutaneous melanoma cell lines and 8/8 ocular melanoma tissues, together with 14/17 cutaneous melanoma tissues screened, expressed the new isoform PAX 3g. All 8 cutaneous melanoma cell lines expressed PAX 3h, but it was not detectable in any of the tumor tissues (0/20). Neither of the 2 ocular melanoma cell lines expressed the 2 new isoforms. Comparison of the different amplicon staining intensities on a gel suggests that PAX 3c and PAX 3d are the predominant transcripts expressed, with relatively low expression of PAX 3e and PAX 3h. We propose that these and the 2 new isoforms we have discovered may be important in oncogenesis and differential diagnosis of melanomas or SCLC.