Despite promising early data, the
natural product dolastatin 10 has not been successful as a single agent in phase II clinical trials. Herein the mechanism of action and efficacy of a synthetic analogue,
auristatin PYE, was investigated in 2 human
colon adenocarcinoma models, DLD-1 and COLO 205. In vivo efficacy was assessed in subcutaneous xenografts following
intravenous administration. Mechanistic studies investigated effects of
auristatin PYE on microtubule disruption using immunocytochemistry, whilst cell cycle effects were studied using flow cytometry. Possible effects on tumour functional blood vasculature were assessed in tumour-bearing mice.
Auristatin PYE was less potent in vitro than
dolastatin 10, but was significantly more effective (p<0.01) in vivo against both tumours. Significant effects on tumour blood vasculature were seen, with optimal shutdown at 6-h post-treatment. Extensive
necrosis became more evident over time
after treatment.
Auristatin PYE caused severe disruption of normal microtubule structure at concentrations and times comparable with the IC50 data, and also instigated a G2/M cell cycle block.
Auristatin PYE was more effective in the DLD-1 and COLO 205 models than
dolastatin 10, with anti-tumour effects mediated through vascular shutdown. These data suggest that
auristatin PYE has good potential as an anti-
cancer agent.