title: Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.
abstract: High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Raab
authors.forename: Sven
authors.initials: S
authors.lastname: Kappel
authors.forename: Andrea
authors.initials: A
authors.lastname: Krämer
authors.forename: Mourad
authors.initials: M
authors.lastname: Sanhaji
authors.forename: Yves
authors.initials: Y
authors.lastname: Matthess
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kurunci-Csacsko
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Nicole
authors.initials: N
authors.lastname: Sänger
authors.forename: Florian
authors.initials: F
authors.lastname: Prinz
authors.forename: Martin Hrabě de
authors.initials: MH
authors.lastname: Angelis
authors.forename: Jost
authors.initials: J
authors.lastname: Seibler
authors.forename: Juping
authors.initials: J
authors.lastname: Yuan
authors.forename: Martin
authors.initials: M
authors.lastname: Bergmann
authors.forename: Rainald
authors.initials: R
authors.lastname: Knecht
authors.forename: Bertolt
authors.initials: B
authors.lastname: Kreft
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000235:genetics; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018628:Gene Dosage / Q000235:genetics; D055785:Gene Knockdown Techniques; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018675:Toxicity Tests / Q000379:methods*; D014162:Transfection; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017931:DNA Primers; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1