Auristatin PYE, a novel synthetic derivative of dolastatin 10, is highly effective in human colon tumour models

Steven D. Shnyder, Patricia A. Cooper, Nicola J. Millington, George Pettit, Michael C. Bibby

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)353-360
Number of pages8
JournalInternational Journal of Oncology
Volume31
Issue number2
StatePublished - Aug 2007

Fingerprint

dolastatin 10
Colon
Neoplasms
Microtubules
Cell Cycle
Phase II Clinical Trials
Biological Products
Heterografts
Intravenous Administration
Inhibitory Concentration 50
Blood Vessels
auristatin PYE
Flow Cytometry
Adenocarcinoma
Necrosis
Immunohistochemistry

Keywords

  • Auristatin PYE
  • Colon adenocarcinoma
  • Dolastatin 10
  • Preclinical
  • Tubulin-binder

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Auristatin PYE, a novel synthetic derivative of dolastatin 10, is highly effective in human colon tumour models. / Shnyder, Steven D.; Cooper, Patricia A.; Millington, Nicola J.; Pettit, George; Bibby, Michael C.

In: International Journal of Oncology, Vol. 31, No. 2, 08.2007, p. 353-360.

Research output: Contribution to journalArticle

Shnyder, Steven D. ; Cooper, Patricia A. ; Millington, Nicola J. ; Pettit, George ; Bibby, Michael C. / Auristatin PYE, a novel synthetic derivative of dolastatin 10, is highly effective in human colon tumour models. In: International Journal of Oncology. 2007 ; Vol. 31, No. 2. pp. 353-360.
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