BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dogprostate cancer model that more fully replicates the features of humanprostate cancer. METHODS: We stably transfected human cDNA of the GRPrbombesin (BBN) receptor subtype to canineAce-1prostate 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 tumormice and dissected organs. RESULTS: Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing humanprostate 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. CONCLUSIONS: The dual tumorAce-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.
Authors: Jill M Keller; George R Schade; Kimberly Ives; Xu Cheng; Thomas J Rosol; Morand Piert; Javed Siddiqui; William W Roberts; Evan T Keller Journal: Prostate Date: 2013-01-17 Impact factor: 4.104
Authors: Karen E Linder; Edmund Metcalfe; Thangavel Arunachalam; Jianqing Chen; Stephen M Eaton; Weiwei Feng; Hong Fan; Natarajan Raju; Aldo Cagnolini; Laura E Lantry; Adrian D Nunn; Rolf E Swenson Journal: Bioconjug Chem Date: 2009-06 Impact factor: 4.774
Authors: Martijn Smeenge; Massimo Mischi; M Pilar Laguna Pes; Jean J M C H de la Rosette; Hessel Wijkstra Journal: World J Urol Date: 2011-08-17 Impact factor: 4.226
Authors: Gesche Wieser; Rosalba Mansi; Anca L Grosu; Wolfgang Schultze-Seemann; Rebecca A Dumont-Walter; Philipp T Meyer; Helmut R Maecke; Jean Claude Reubi; Wolfgang A Weber Journal: Theranostics Date: 2014-02-01 Impact factor: 11.556
Authors: Michael F Tweedle; Haiming Ding; William T Drost; Joshua Dowell; James Spain; Mathew Joseph; Said M Elshafae; Maria-Isabela Menendez; Li Gong; Shankaran Kothandaraman; Wessel P Dirksen; Chadwick L Wright; Robert Bahnson; Michael V Knopp; Thomas J Rosol Journal: Prostate Date: 2018-07-11 Impact factor: 4.104