Key Points
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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.
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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.
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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.
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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.
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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).
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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.
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Factors in the tumour microenvironment are likely to influence the susceptibility of tumour blood vessels to VDAs and this is currently under investigation.
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Other low-molecular-weight VDAs currently under development include several other natural and synthetic combretastatins, other tubulin-binding agents and inhibitors of junctional proteins.
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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.
Abstract
Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) — one of a structurally distinct group of drugs — is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.
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Acknowledgements
Research from the first two authors who contributed to this review was carried out at the Gray Cancer Institute in London, United Kingdom, and we are grateful to the Institute for providing all the necessary facilities for this work. We would also like to thank all our past and present colleagues at the Gray Cancer Institute, Mount Vernon Hospital, the Auckland Cancer Society Research Centre and elsewhere, who collaborated in our research that contributed to this review. The authors' work is supported by grants from Cancer Research UK (G.M.T and C.K.) and the Auckland Division of the Cancer Society of New Zealand (B.C.B.).
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Glossary
- AMINOPEPTIDASE
-
An enzyme involved in protein degradation that hydrolyses peptides by acting on the peptide bond next to a terminal amino acid containing a free amino group.
- ECTOPICALLY
-
In an abnormal place, in this case outside the tissue of origin.
- ORTHOTOPICALLY
-
In the normal place, in this case within the tissue of origin.
- DOSE POTENT
-
Very effective for a given dose.
- BLEB
-
An actin-lined cell-surface protrusion.
- HAEMATOCRIT
-
The ratio of the volume of packed red blood cells to the volume of whole blood.
- ROULEAUX
-
A group of red blood cells resembling a stack of coins.
- PROTEIN EXTRAVASATION
-
Movement of blood-borne protein across the vascular wall into the tissue interstitium.
- PARACELLULAR PERMEABILITY
-
Permeability associated with solute or water transport between cells.
- TRANSCELLULAR PERMEABILITY
-
Permeability associated with solute or water transport across the cells themselves.
- PLATELET ACTIVATION
-
Processes involved with initiating the platelet's contribution to blood clotting.
- RHEOLOGICAL
-
Relating to the flowing of red cells.
- PERICYTES
-
Cells of the connective tissue strongly associated with small blood vessels.
- VASOVAGAL SYNCOPE
-
A usually transitory condition that is marked by anxiety, nausea, respiratory distress and fainting, and that is believed to be due to joint vasomotor and vagal disturbances.
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Tozer, G., Kanthou, C. & Baguley, B. Disrupting tumour blood vessels. Nat Rev Cancer 5, 423–435 (2005). https://doi.org/10.1038/nrc1628
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DOI: https://doi.org/10.1038/nrc1628
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