Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.

Monika Raab; Sven Kappel; Andrea Krämer; Mourad Sanhaji; Yves Matthess; Elisabeth Kurunci-Csacsko; Julia Calzada-Wack; Birgit Rathkolb; Jan Rozman; Thure Adler; Dirk H Busch; Irene Esposito; Helmut Fuchs; Valérie Gailus-Durner; Martin Klingenspor; Eckhard Wolf; Nicole Sänger; Florian Prinz; Martin Hrabě de Angelis; Jost Seibler; Juping Yuan; Martin Bergmann; Rainald Knecht; Bertolt Kreft; Klaus Strebhardt

doi:10.1038/ncomms1395

Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.

Standard

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, Jahrgang 2, 2011, S. 395.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Raab, M, Kappel, S, Krämer, A, Sanhaji, M, Matthess, Y, Kurunci-Csacsko, E, Calzada-Wack, J, Rathkolb, B, Rozman, J, Adler, T, Busch, DH, Esposito, I, Fuchs, H, Gailus-Durner, V, Klingenspor, M, Wolf, E, Sänger, N, Prinz, F, Angelis, MHD, Seibler, J, Yuan, J, Bergmann, M, Knecht, R, Kreft, B & Strebhardt, K 2011, 'Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.', NAT COMMUN, Jg. 2, S. 395. https://doi.org/10.1038/ncomms1395

APA

Raab, M., Kappel, S., Krämer, A., Sanhaji, M., Matthess, Y., Kurunci-Csacsko, E., Calzada-Wack, J., Rathkolb, B., Rozman, J., Adler, T., Busch, D. H., Esposito, I., Fuchs, H., Gailus-Durner, V., Klingenspor, M., Wolf, E., Sänger, N., Prinz, F., Angelis, M. H. D., ... Strebhardt, K. (2011). Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells. NAT COMMUN, 2, 395. https://doi.org/10.1038/ncomms1395

Vancouver

Raab M, Kappel S, Krämer A, Sanhaji M, Matthess Y, Kurunci-Csacsko E et al. Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells. NAT COMMUN. 2011;2:395. https://doi.org/10.1038/ncomms1395

Bibtex

@article{7c4f737056d94a639aa6ab3c5ece9c44,

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.",

keywords = "Animals, Humans, Cells, Cultured, Mice, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Northern, Gene Knockdown Techniques, Flow Cytometry, Mice, Transgenic, Fluorescent Antibody Technique, Transfection, Drug Evaluation, Preclinical, Apoptosis/genetics, DNA Primers/genetics, Toxicity Tests/*methods, Antineoplastic Agents/*toxicity, Cell Cycle Proteins/*antagonists & inhibitors/genetics/metabolism, Gene Dosage/genetics, Genetic Engineering/methods, Neoplasms/*drug therapy, Protein-Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism, Proto-Oncogene Proteins/*antagonists & inhibitors/genetics/metabolism, RNA Interference/*drug effects, Animals, Humans, Cells, Cultured, Mice, Reverse Transcriptase Polymerase Chain Reaction, Blotting, Northern, Gene Knockdown Techniques, Flow Cytometry, Mice, Transgenic, Fluorescent Antibody Technique, Transfection, Drug Evaluation, Preclinical, Apoptosis/genetics, DNA Primers/genetics, Toxicity Tests/*methods, Antineoplastic Agents/*toxicity, Cell Cycle Proteins/*antagonists & inhibitors/genetics/metabolism, Gene Dosage/genetics, Genetic Engineering/methods, Neoplasms/*drug therapy, Protein-Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism, Proto-Oncogene Proteins/*antagonists & inhibitors/genetics/metabolism, RNA Interference/*drug effects",

author = "Monika Raab and Sven Kappel and Andrea Kr{\"a}mer and Mourad Sanhaji and Yves Matthess and Elisabeth Kurunci-Csacsko and Julia Calzada-Wack and Birgit Rathkolb and Jan Rozman and Thure Adler and Busch, {Dirk H} and Irene Esposito and Helmut Fuchs and Val{\'e}rie Gailus-Durner and Martin Klingenspor and Eckhard Wolf and Nicole S{\"a}nger and Florian Prinz and Angelis, {Martin Hrab{\v e} de} and Jost Seibler and Juping Yuan and Martin Bergmann and Rainald Knecht and Bertolt Kreft and Klaus Strebhardt",

year = "2011",

doi = "10.1038/ncomms1395",

language = "English",

volume = "2",

pages = "395",

journal = "NAT COMMUN",

issn = "2041-1723",

publisher = "NATURE PUBLISHING GROUP",

}

RIS

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