Auristatin PYE, a novel synthetic derivative of dolastatin 10, is highly effective in human colon tumour models.
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.
Shnyder
Steven D
SD
Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK. s.d.shnyder@bradford.ac.uk
Cooper
Patricia A
PA
Millington
Nicola J
NJ
Pettit
G Robert
GR
Bibby
Michael C
MC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009336:Necrosis; D009368:Neoplasm Transplantation
D000970:Antineoplastic Agents; D047630:Depsipeptides; C523392:auristatin PYE; C064570:dolastatin 10