Vascular disrupting agents in clinical development

Abstract

Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma

“…The consequence of this is the appearance of central necrosis with a viable peripheral rim of tumour cells, leading to rapid repopulation of tumours and the consequent failure to achieve significant tumour growth delay (Tozer et al, 2005). Major vascular disrupting agents that have been tested in clinical phase I studies include CA-4-P, DMXAA, ZD6126, AVE8062 and ABT-751 (Hinnen and Eskens, 2007;Patterson and Rustin, 2007). The combination of vascular disrupting agents with other treatment modalities, such as radiotherapy or chemotherapy, leads to increased antitumour effect of these combined treatments (Tozer et al, 2005;Patterson and Rustin, 2007).…”

Modulation of in Vivo Tumor Radiation Response via Gold Nanoshell-Mediated Vascular-Focused Hyperthermia: Characterizing an Integrated Antihypoxic and Localized Vascular Disrupting Targeting Strategy

“…Vascular disrupting agents in preclinical and early clinical development include combretastatin A4 phosphate (CA4P), ZD6126, TZT-1027, AVE8062, ABT-751, and MN-029, which target the tubulin cytoskeletal network of endothelial cells, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which targets autocrine endothelial regulatory cascades, and Exherin (AFH-1), which targets cell adhesion. [27][28][29][30][31][32][33] While these agents have shown promise in early trials, there is concern that more than just tumor vessels may be targeted by systemic exposure to these agents. In particular, damage to vascular compartments outside the tumor may contribute to acute coronary syndromes and thromboembolic events.…”

A highly efficient and tumor vascular-targeting therapeutic technique with size-expansible gadofullerene nanocrystals

“…The explosive volume expansion accompanying with the possible rotation of the magnetic nanocrystals can thus destroy the networks of endothelia cells and abscission from the basilemma. The It is noted that this function is similar to what the vascular disrupting agents (VDAs) have, namely to alter the shape of the endothelial cell by disrupting the cytoskeleton and cellto-cell junctions [30,31]. However, the RF-assisted GFNCs offers a physio-therapeutic technique that relies on the inherent pure physical properties of tumor vasculatures to avoid uncontrollable biochemical response introduced by conventional VDAs [32].…”