R. Wild et al., Inhibition of angiogenesis and tumour growth by VEGF121-toxin conjugate: differential effect on proliferating endothelial cells, BR J CANC, 83(8), 2000, pp. 1077-1083
Vascular endothelial growth factor (VEGF) plays an important role in tumour
angiogenesis. VEGF binds to tyrosine kinase receptors, which are expressed
almost exclusively on tumour endothelium. Therefore, VEGF can be used to t
arget toxin molecules to tumour vessels for anti-angiogenic therapy. Howeve
r, recent evidence suggests that VEGF can also bind in an isoform-specific
fashion to a newly identified neuropilin-1 (NP-I) receptor. NP-1 is widely
expressed in normal tissue and presents a potential target for unwanted tox
icity. As a consequence, we investigated whether the VEGF121 isoform, which
lacks the NP-1 binding domain, could be used to target toxin polypeptides
to tumour vasculature, Treatment of endothelial cells with a VEGF121-diphth
eria toxin (DT385) conjugate selectively inhibited proliferating endothelia
l cells, whereas confluent cultures were completely resistant to the constr
uct. In addition, VEGF121-DT385 conjugate treatment completely prevented tu
mour cell induced angiogenesis in vivo. Most importantly, the conjugate inh
ibited tumour growth in athymic mice and induced tumour-specific vascular d
amage. There was also no apparent toxicity associated with the treatment. O
ur results suggest that proliferating endothelial cells are highly sensitiv
e to VEGF121-toxin conjugates and that the binding to NP-1 receptors is not
necessary for efficient inhibition of tumour growth. (C) 2000 Cancer Resea
rch Campaign.