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
beta-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.