Vascular Disrupting Agents (VDAs) are a novel class of drugs that target the blood supply of a tumour. Normal tissues of the body maintain their blood supply by an orderly and efficient vascular network. These networks are organised with mature, evenly distributed, vessels to allow adequate circulation of oxygen and other nutrients to all cells.
Conversely, the vasculature, supply of vessels to a specific region, of solid tumours is fundamentally different. Tumour angiogenesis, the process of developing new blood vessels, which is required for tumour growth and metastatic spread, involves several processes, including growth, reproduction and movement of cells that line the interior surface of blood vessels, known as vascular endothelial cells. This leads to the formation of a functioning vessel with an opening. Without angiogenesis, tumour growth is restricted to about 1mm from the blood vessel due to lack of oxygen and nutrients. For further growth, they must develop a blood supply network, which differs from that found in normal tissue in that it is primitive in nature structure, and functionally abnormal.
Due to the importance of vasculature for the development and growth of tumours, it has received a great deal of interest as a possible therapeutic target, which has lead to the evolution of a novel class of drugs known as Vascular Disrupting Agents (VDAs). VDAs exploit known differences between blood vessels of tumours and normal tissues, which allows them to selectively block or rapidly destroy pre-existing vessels of tumours. Ultimately shutting down the tumour’s blood supply, thereby depriving them of the oxygen and nutrients they need to survive. VDAs can be divided into two categories: (1) biologics, such as antibodies and peptides that deliver toxins, effectors that promote the coagulation of blood (procoagulant) and agents which encourage programmed cell death (proapoptotic) to the tumour endothelium, and (2) small-molecule agents which exploit known differences between tumour and normal blood vessels to induce selective vascular dysfunction. Minutes after VDA exposure, affected tumour blood vessels begin to show signs of damage leading to a marked reduction in blood flow and ultimately tumour cell death and secondary cell death as a result of prolonged lack of oxygen.
One limitation following VDA treatment is that a residual rim remains around the tumour boundary that most likely derives nutritional support from surrounding normal tissue vasculature and is therefore less susceptible to VDAs. Considering these cells can act as a source of tumour regrowth, VDAs are thought to be most efficient when combined with other treatments. Significant improvements were found in anti-tumour activity when VDAs were given within a few hours after administration of conventional chemotherapy/radiotherapy in a variety of tumour models. When VDAs were administered prior to conventional compounds, no improvement was seen and may be explained by impairment of tumour vasculature leading to lack of delivery of subsequent chemotherapeutic agents. VDAs are currently being tested in human trials, which are showing promising results in the treatment of advanced non-small cell lung cancer (NSCLC) and an aggressive, treatment resistant, thyroid cancer known as anaplastic thyroid carcinoma (ATC).
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