Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.
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Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells. / Raab, Monika; Kappel, Sven; Krämer, Andrea; Sanhaji, Mourad; Matthess, Yves; Kurunci-Csacsko, Elisabeth; Calzada-Wack, Julia; Rathkolb, Birgit; Rozman, Jan; Adler, Thure; Busch, Dirk H; Esposito, Irene; Fuchs, Helmut; Gailus-Durner, Valérie; Klingenspor, Martin; Wolf, Eckhard; Sänger, Nicole; Prinz, Florian; Angelis, Martin Hrabě de; Seibler, Jost; Yuan, Juping; Bergmann, Martin; Knecht, Rainald; Kreft, Bertolt; Strebhardt, Klaus.
In: NAT COMMUN, Vol. 2, 2011, p. 395.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.
AU - Raab, Monika
AU - Kappel, Sven
AU - Krämer, Andrea
AU - Sanhaji, Mourad
AU - Matthess, Yves
AU - Kurunci-Csacsko, Elisabeth
AU - Calzada-Wack, Julia
AU - Rathkolb, Birgit
AU - Rozman, Jan
AU - Adler, Thure
AU - Busch, Dirk H
AU - Esposito, Irene
AU - Fuchs, Helmut
AU - Gailus-Durner, Valérie
AU - Klingenspor, Martin
AU - Wolf, Eckhard
AU - Sänger, Nicole
AU - Prinz, Florian
AU - Angelis, Martin Hrabě de
AU - Seibler, Jost
AU - Yuan, Juping
AU - Bergmann, Martin
AU - Knecht, Rainald
AU - Kreft, Bertolt
AU - Strebhardt, Klaus
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Blotting, Northern
KW - Gene Knockdown Techniques
KW - Flow Cytometry
KW - Mice, Transgenic
KW - Fluorescent Antibody Technique
KW - Transfection
KW - Drug Evaluation, Preclinical
KW - Apoptosis/genetics
KW - DNA Primers/genetics
KW - Toxicity Tests/methods
KW - Antineoplastic Agents/toxicity
KW - Cell Cycle Proteins/antagonists & inhibitors/genetics/metabolism
KW - Gene Dosage/genetics
KW - Genetic Engineering/methods
KW - Neoplasms/drug therapy
KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
KW - Proto-Oncogene Proteins/antagonists & inhibitors/genetics/metabolism
KW - RNA Interference/drug effects
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Blotting, Northern
KW - Gene Knockdown Techniques
KW - Flow Cytometry
KW - Mice, Transgenic
KW - Fluorescent Antibody Technique
KW - Transfection
KW - Drug Evaluation, Preclinical
KW - Apoptosis/genetics
KW - DNA Primers/genetics
KW - Toxicity Tests/methods
KW - Antineoplastic Agents/toxicity
KW - Cell Cycle Proteins/antagonists & inhibitors/genetics/metabolism
KW - Gene Dosage/genetics
KW - Genetic Engineering/methods
KW - Neoplasms/drug therapy
KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
KW - Proto-Oncogene Proteins/antagonists & inhibitors/genetics/metabolism
KW - RNA Interference/drug effects
U2 - 10.1038/ncomms1395
DO - 10.1038/ncomms1395
M3 - SCORING: Journal article
VL - 2
SP - 395
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -