title: Pharmacology of the novel antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2): observation of a U-shaped dose-response curve in several preclinical models of angiogenesis and tumor growth.
abstract: OBJECTIVE
  ATN-161 (Ac-PHSCN-NH(2)) 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.
  
  
  METHODS
  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 beta 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 alpha(5)beta(1)-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 1 to 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.
authors.affiliation: Attenuon, LLC, San Diego, California 92121, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Doñate
authors.forename: Graham C
authors.initials: GC
authors.lastname: Parry
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Harvey
authors.initials: H
authors.lastname: Hensley
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Guan
authors.forename: Ivy
authors.initials: I
authors.lastname: Beck
authors.forename: Ziva
authors.initials: Z
authors.lastname: Tel-Tsur
authors.forename: Marian L
authors.initials: ML
authors.lastname: Plunkett
authors.forename: Mari
authors.initials: M
authors.lastname: Manuia
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D009842:Oligopeptides; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide