Potent anti-metastatic activity of combretastatin-A4.
The requirement for tumour vascularisation to permit the expansion of solid tumours beyond a threshold size of approximately 1 mm diameter has focussed attention on anti-vascular and anti-angiogenic agents for cancer therapy. Combretastatin-A4 (cis CA-4P) is a tubulin-binding agent that is cytotoxic for proliferating endothelial cells in vitro and causes anti-vascular effects in the established tumour vessels of some primary tumours. Preliminary data from Phase I clinical trials indicate that cis CA-4 may also be effective in targeting the vasculature of human tumours. As metastatic disease is the principal cause of mortality in cancer, we have investigated the effects of cis CA-4 on metastatic development using an in vivo model. We show that bolus or continuous administration of cis CA-4P results in potent inhibition of metastases derived from ectopic primary Lewis lung carcinomas in mice whereas the trans CA-4 isomer is without effect. These data further characterise the activity of CA-4 in vivo and suggest that the drug should be evaluated clinically as an anti-metastatic agent.
Griggs
J
J
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Brindle
K M
KM
Metcalfe
J C
JC
Hill
S A
SA
Smith
G A
GA
Beauregard
D A
DA
Hesketh
R
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D007124:Immunoenzyme Techniques; D008168:Lung / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013267:Stilbenes / Q000627:therapeutic use*; D014841:von Willebrand Factor / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D014841:von Willebrand Factor; C058728:fosbretabulin