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In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug
Authors
A Bujaski
AL Laws
+36 more
AM Schor
AT McGown
BA Chabner
BA Warren
BC Baguley
DJ Chaplin
E Borenfreund
E Jaffe
EK Rowinsky
GG Dark
GR Pettit
GR Pettit
GW Rewcastle
HF Dvorak
J Egawa
JA Double
JA Double
JA Woods
KA Smith
LM Ching
MC Bibby
MC Bibby
MC Bibby
MC Bibby
MC Bibby
P Vaupel
PA Clearkin
PB Schiff
PB Schiff
R Montesano
RI Geran
SA Hill
SE Cowen
T Maciag
V Mahadevan
W Birchmeier
Publication date
Publisher
Nature Publishing Group
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PubMed
Abstract
The anti-tumour effects and mechanism of action of combretastatin A-4 and its prodrug, combretastatin A-4 disodium phosphate, were examined in subcutaneous and orthotopically transplanted experimental colon tumour models. Additionally, the ability of these compounds to directly interfere with endothelial cell behaviour was also examined in HUVEC cultures. Combretastatin A-4 (150 mg kg–1, intraperitoneally (i.p.)) and its water-soluble prodrug (100 mg kg–1, i.p.) caused almost complete vascular shutdown (at 4 h), extensive haemorrhagic necrosis which started at 1 h after treatment and significant tumour growth delay in MAC 15A subcutaneous (s.c.) colon tumours. Similar vascular effects were obtained in MAC 15 orthotopic tumours and SW620 human colon tumour xenografts treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic deposits but not in avascular secondary deposits. The possible mechanism giving rise to these effects was examined in HUVEC cells. Here cellular networks formed in type I calf-skin collagen layers and these networks were completely disrupted when incubated with a non-cytotoxic concentration of combretastatin A-4 or its prodrug. This effect started at 4 h and was complete by 24 h. The same non-cytotoxic concentrations resulted in disorganization of F-actin and β-tubulin at 1 h after treatment. In conclusion, combretastatin A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthotopic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action. © 1999 Cancer Research Campaig
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Last time updated on 04/12/2019