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A large group of tubulin-binding microtubule-depolymerizing agents act as tumour vascular disrupting agents (VDAs). Several members of this group are now in clinical trials in combination with conventional anticancer drugs and radiotherapy. Here we briefly update on the development of tubulin-binding combretastatins as VDAs, summarize what is known of their mechanisms of action and address issues relating to treatment resistance, using disodium combretastatin A-4 3-O-phosphate (CA-4-P) as an example. Characteristically, VDAs cause a rapid shutdown of blood flow to tumour tissue with much less effect in normal tissues. However, the tumour rim is relatively resistant to treatment. Hypoxia (or hypoxia reoxygenation) induces upregulation of genes associated with angiogenesis and drug resistance. It may be possible to take advantage of treatment-induced hypoxia by combining with drugs that are activated under hypoxic conditions. In summary, VDAs provide a novel approach to cancer treatment, which should effectively complement standard treatments, if treatment resistance is addressed by judicious combination treatment strategies.

Original publication

DOI

10.1259/bjr/36205483

Type

Journal article

Journal

Br J Radiol

Publication Date

10/2008

Volume

81 Spec No 1

Pages

S12 - S20

Keywords

Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Phytogenic, Blood Vessels, Combined Modality Therapy, Drug Resistance, Neoplasm, Humans, Mice, Microtubules, Neoplasms, Rats, Stilbenes, Tubulin Modulators