Fluorescence lifetime imaging microscopy of chemotherapy-induced apoptosis resistance in a syngenic mouse tumor model
M. Keese
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany
The first two authors contributed equally to this work.
Search for more papers by this authorV. Yagublu
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany
The first two authors contributed equally to this work.
Search for more papers by this authorK. Schwenke
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
Max-Planck-Institut für Molekulare Physiologie, Abteilung Systemische Zellbiologie, 44227 Dortmund, Germany
Search for more papers by this authorS. Post
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
Search for more papers by this authorCorresponding Author
P. Bastiaens
European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany
Max-Planck-Institut für Molekulare Physiologie, Abteilung Systemische Zellbiologie, 44227 Dortmund, Germany
Tel: +49 (231) 133-2200, Fax: +49 (231) 133-2299
MPI für Molekulare Physiologie Otto-Hahn-Straße 11, D-44227 DortmundSearch for more papers by this authorM. Keese
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany
The first two authors contributed equally to this work.
Search for more papers by this authorV. Yagublu
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany
The first two authors contributed equally to this work.
Search for more papers by this authorK. Schwenke
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
Max-Planck-Institut für Molekulare Physiologie, Abteilung Systemische Zellbiologie, 44227 Dortmund, Germany
Search for more papers by this authorS. Post
Chirurgische Klinik, Universitätsklinikum Mannheim, 68167 Mannheim, Germany
Search for more papers by this authorCorresponding Author
P. Bastiaens
European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany
Max-Planck-Institut für Molekulare Physiologie, Abteilung Systemische Zellbiologie, 44227 Dortmund, Germany
Tel: +49 (231) 133-2200, Fax: +49 (231) 133-2299
MPI für Molekulare Physiologie Otto-Hahn-Straße 11, D-44227 DortmundSearch for more papers by this authorAbstract
During cancer therapy with DNA-damaging drug-agents, the development of secondary resistance to apoptosis can be observed. In the search for novel therapeutic approaches that can be used in these cases, we monitored chemotherapy-induced apoptosis resistance in a syngenic mouse tumor model. For this, syngenic murine colorectal carcinoma cells, which stably expressed a FRET-based caspase-3 activity sensor, were introduced into animals to induce peritoneal carcinomatosis or disseminated hepatic metastases. This syngenic system allowed in vitro, in vivo and ex vivo analysis of chemotherapy induced apoptosis induction by optically monitoring the caspase-3 sensor state in the tumor cells. Tumor tissue analysis of 5-FU treated mice showed the selection of 5-FU-induced apoptosis resistant tumor cells. These and chemo-naive fluorescent tumor cells could be re-isolated from treated and untreated mice and propagated in cell culture. Re-exposure to 5-FU and second line treatment modalities in this ex-vivo setting showed that 5-FU induced apoptosis resistance could be alleviated by imatinib mesylate (Gleevec). We thus show that syngenic mouse systems that stably express a FRET-based caspase-3 sensor can be employed to analyse the therapeutic efficiency of apoptosis inducing chemotherapy.
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