What are vascular disrupting agents (VDA) and how are they different from vascular targeting agents (VTA)?<\/em><\/strong><\/p>\n VTAs inhibit the formation of new blood vessels<\/a>, but do not act on already existing blood vessels, therefore, they prevent neo-vascularizationVDAs target endothelial cells and pericytes of the already established tumor vessels, leading to tumor ischemia and necrosis. VDA\u2019s are more efficient in advanced disease and can be administered acutely. Although the mechanism of action of VDAs is not well understood, they destroy the endothelium of the solid tumors vasculature, thereby starving tumor cells of oxygen and other nutrients needed to thrive.<\/p>\n What is CA4P and how does it work?<\/em><\/strong><\/p>\n Combretastatin A4-Phosphate (CA4P \u2013 prodrug of combretastatin A-4) comes from the family of chemicals that have been extracted originally from the \u201cCombretum Caffrum<\/em><\/a>,<\/em>\u201d<\/em> the African willow tree. This is the most widely studied VDA and the first such agent to enter clinical trials; it is the lead product candidate of Oxigene, now Mateon Therapeutics.<\/p>\n Figure 1: Chemical structure (ME = methyl group)<\/p><\/div>\n It acts by reversibly binding to tubulin, thereby changing the endothelial cell structure; this ultimately leads to occlusion of tumor blood supply, which causes widespread ischemia and necrosis of tumor cells within the core of the tumor as shown in the Figures 2 and 3.<\/p>\n Figure 2: VDA\u2019s directly binding to tubulin, reversibly, which changes endothelial cell structure leading to occlusion of blood vessels. Mateon Therapeutics<\/a><\/p><\/div>\n Figure 3: SEM (scanning electron microscope) of corrosion casts on liver metastasis. Untreated (left) figure shows dense tumor vessels at host-tumor interface. The right figure shows marked reduction of the patient\u2019s tumor vasculature post treating with CA4P 100mg\/kg. Mateon Therapeutics<\/a><\/p><\/div>\n Rationale for combining CA4P with classic anti-angiogenic therapy<\/em><\/strong><\/p>\n Currently available classic anti-angiogenic drugs (VTAs) inhibit the formation of VEGF-driven new blood vessels. Avastin (bevacizumab) is the prototypic antiangiogenic drug – it is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Since VEGF is the key angiogenic factor in tumors, blocking VEGF signal transduction can lead to tumor growth arrest and inhibition of metastasis. Avastin is the first antiangiogenic agent to demonstrate a survival benefit in patients with any type of cancer.<\/p>\n Although VDAs cause acute occlusion of existing vessels causing intra-tumor necrosis, CA4P treated tumors were left with a peripheral rim of viable tumor cells, which rely on surrounding blood vessels<\/a> as seen in Fig 4. \u00a0This residual viable rim of peripheral tumor cells allowed re-growth and re-vascularization of the tumor.<\/a> \u00a0It was proposed that VDA treatment led to an acute mobilization of circulating endothelial progenitor (CEP) cells, which home to the viable tumor rim, otherwise found in low numbers in the untreated cancer. For this reason Mateon therapeutics combined CA4P with bevacizumab<\/a>.\u00a0 This combination of CA4P with VEGF inhibitors is the current focus of Mateon therapeutics.<\/a><\/p>\n Figure 4: Hematoxylin and eosin staining of histological sections of murine adenocarcinoma CaNT tumors, pre and post treatment with 100mg\/kg CA4P. The peripheral vascular rim of viable tumor cells are seen clearly 3 days post CA4P treatment. Mateon Therapeutics<\/a><\/p><\/div>\n![\"Figure](\"http:\/\/blogs.shu.edu\/cancer\/files\/2016\/10\/Fig-1-Combrestatin.png\")
<\/a>![\"Figure](\"http:\/\/blogs.shu.edu\/cancer\/files\/2016\/10\/Figure-2-occlusion.jpg\")
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<\/a>![\"Figure](\"http:\/\/blogs.shu.edu\/cancer\/files\/2016\/10\/Fig-4-Tumor-Rim-Viability.png\")
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