In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug

The anti-tumour effects and mechanism of action of combretastatin A-4 and i ts prodrug, combretastatin A-4 disodium phosphate, were examined in subcuta neous and orthotopically transplanted experimental colon tumour models. Add itionally, the ability of these compounds to directly interfere with endoth elial 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), ext ensive haemorrhagic necrosis which started at 1 h after treatment and signi ficant tumour growth delay in MAC 15A subcutaneous (s.c.) colon rumours. Si milar vascular effects were obtained in MAC 15 orthotopic rumours and SW620 human colon tumour xenograits treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic depo sits 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 complete ly disrupted when incubated with a non-cytotoxic concentration of combretas tatin 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, combretastati n A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthoto pic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action. (C) 1999 Cancer Research Campaign.