Disrupting tumour blood vessels

Abstract

Solid tumours require a functional blood supply for their continued growth, and the established tumour vasculature is therefore an attractive target for therapy. Low-molecular-weight vascular-disrupting agents (VDAs) cause the rapid and selective shutdown of tumour blood flow. The combretastatins and drugs related to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are the two main groups of VDAs that are currently in preclinical and clinical development. In endothelial cells in culture, combretastatin A-4 3-O-phosphate (CA-4-P; the lead combretastatin) and DMXAA cause rapid re-organization of the actin cytoskeleton, mediated by disruption of the tubulin cytoskeleton for CA-4-P but not DMXAA. An increase in vascular permeability is likely to be an important component of the mechanisms that lead to the shutdown of tumour blood flow by both classes of drug. Signalling pathways associated with CA-4-P and their effects on permeability involve the small GTPase RHO and RHO kinase, as well as stress-activated protein kinase 2 (SAPK2). The basis for the susceptibility of the tumour vasculature to the VDAs that are currently in preclinical and clinical development is unclear, although there is evidence that, across different tumour types, increased susceptibility correlates with increased permeability of tumour blood vessels. Factors in the tumour microenvironment are likely to influence the susceptibility of tumour blood vessels to VDAs and this is currently under investigation. Other low-molecular-weight VDAs currently under development include several other natural and synthetic combretastatins, other tubulin-binding agents and inhibitors of junctional proteins. Phase I and II clinical trials have confirmed the tumour selectivity of CA-4-P and DMXAA in the clinical setting. The therapeutic potential of VDAs lies in their combination with conventional and/or other novel cancer treatments; such combinations are currently being tested in clinical trials involving radiotherapy, chemotherapy and radioimmunotherapy.