The biology of the combretastatins as tumour vascular targeting agents.
The tumour vasculature is an attractive target for therapy. Combretastatin A-4 (CA-4) and A-1 (CA-1) are tubulin binding agents, structurally related to colchicine, which induce vascular-mediated tumour necrosis in animal models. CA-1 and CA-4 were isolated from the African bush willow, Combretum caffrum, and several synthetic analogues are also now available, such as the Aventis Pharma compound, AVE8062. More soluble, phosphated, forms of CA-4 (CA-4-P) and CA-1 (CA-1-P) are commonly used for in vitro and in vivo studies. These are cleaved to the natural forms by endogenous phosphatases and are taken up into cells. The lead compound, CA-4-P, is currently in clinical trial as a tumour vascular targeting agent. In animal models, CA-4-P causes a prolonged and extensive shut-down of blood flow in established tumour blood vessels, with much less effect in normal tissues. This paper reviews the current understanding of the mechanism of action of the combretastatins and their therapeutic potential.
Tozer
Gillian M
GM
Gray Cancer Institute, PO Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, UK. tozer@gci.ac.uk
Kanthou
Chryso
C
Parkins
Charles S
CS
Hill
Sally A
SA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001632:Bibenzyls / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013267:Stilbenes / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D013267:Stilbenes; C040105:combretastatin; C058728:fosbretabulin