Pharmacology of the novel antiangiogenic peptide ATN-161 (Ac-PHSCN-NH 2): Observation of a U-shaped dose-response curve in several preclinical models of angiogenesis and tumor growth

Fernando Doñate, Graham C. Parry, Yuval Shaked, Harvey Hensley, Xiaojun Guan, Ivy Beck, Ziva Tel-Tsur, Marian L. Plunkett, Mari Manuia, David E. Shaw, Robert S. Kerbel, Andrew P. Mazar

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Purpose: ATN-161 (Ac-PHSCN-NH2) is an integrin-binding peptide that is currently in phase II trials in cancer patients. This peptide has been shown to have antitumor activity in a number of different preclinical models. Experimental Design: In this study, we examined the binding, biodistribution, and dose and biomarker response of ATN-161 in several animal models. Results: ATN-161 bound to the β subunit of a number of different integrins implicated in tumor growth and progression, which depended on its cysteine thiol. The peptide had antiangiogenic activity in the Matrigel plug model, and this activity could be reversed by inhibitors of protein kinase A, an effector of α5β1-dependent angiogenesis. A labeled analogue of ATN-161, ATN-453, localized to neovessels but not to preexisting vasculature in vivo. The half-life of the peptide when localized to a tumor was much longer than in plasma. Dose-response studies in the Matrigel plug model of angiogenesis or a Lewis lung carcinoma model of tumor growth showed a U-shaped dose-response curve with 1to 10 mg/kg given thrice a week, being the optimal dose range of ATN-161. Two additional pharmacodynamic models of angiogenesis (dynamic contrast-enhanced magnetic resonance imaging and measurement of endothelial cell progenitors) also revealed U-shaped dose-response curves. Conclusions:The presence of a U-shaped dose-response curve presents a significant challenge to identifying a biologically active dose of ATN-161. However, the identification of biomarkers of angiogenesis that also exhibit this same U-shaped response should allow the translation of those biomarkers to the clinic, allowing them to be used to identify the active dose of ATN-161 in phase II studies.

Original languageEnglish (US)
Pages (from-to)2137-2144
Number of pages8
JournalClinical Cancer Research
Issue number7
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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