title: A human GRPr-transfected Ace-1 canine prostate cancer model in mice.
abstract: A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer.
  
  
  
  We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy. A dual tumor nude mouse xenograft model was developed from Ace-1(CMV) (vector transfected Ace-1) and Ace-1(huGRPr) cells. The model was used to explore the in vivo behavior of two new IRDye800-labeled GRPr binding optical imaging agents: 800-G-Abz4-t-BBN, from a GRPr agonist peptide, and 800-G-Abz4-STAT, from a GRPr antagonist peptide, by imaging the tumor mice and dissected organs.
  
  
  
  Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing human prostate cancer cell line, with 4-13 nM IC50 against (125) I-Tyr(4) -BBN, but did not bind Ace-1(CMV) cells (vector transfected). Binding was blocked by bombesin. Ca(2+) activation assays demonstrated that Ace-1(huGPRr) expressed biologically active GRPr. Both Ace-1 cell lines grew in the flanks of 100% of the nude mice and formed tumors of ∼0.5 cm diameter in 1 week. In vivo imaging of the mice at 800 nm emission showed GRPr+: GRPr- tumor signal brighter by a factor of two at 24 h post IV administration of 10 nmol of the imaging agents. Blood retention (4-8% ID at 1 h) was greater by a factor >10 and cumulative urine accumulation (28-30% at 4 h) was less by a factor 2 compared to a radioactive analog of the t-BBN containing agent, (177) LuAMBA, probably due to binding to blood albumin, which we confirmed in a mouse serum assay.
  
  
  
  The dual tumor Ace-1(CMV) /Ace-1(huGRPr) model system provides a rapid test of specific to nonspecific binding of new GRPr avid agents in a model that will extend logically to the known Ace-1 orthotopic canine prostate cancer model. Prostate 76:783-795, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Radiology, The Wright Center for Innovation in Biomolecular Imaging, The Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Haiming
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Radiology, The Wright Center for Innovation in Biomolecular Imaging, The Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Shankaran
authors.initials: S
authors.lastname: Kothandaraman
authors.affiliation: Department of Radiology, The Wright Center for Innovation in Biomolecular Imaging, The Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Radiology, The Wright Center for Innovation in Biomolecular Imaging, The Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Williams
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
authors.forename: Wessel P
authors.initials: WP
authors.lastname: Dirksen
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: Department of Radiology, The Wright Center for Innovation in Biomolecular Imaging, The Wexner Medical Center, The Ohio State University, Columbus, Ohio.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Tweedle
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D018004:Receptors, Bombesin / Q000235:genetics
chemical_list: D018004:Receptors, Bombesin
keywords: GRP; NIRF imaging; bombesin; canine prostate cancer