Untersuchung des Wirkungsmechanismus von klassischen antiproliferativen Zytostatika mittels intravitaler Mikroskopie in Mäusen

• Antragsteller: Dr. Stefan Florian
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2012 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 221468111

• Erstellungsjahr: 2016

Zusammenfassung der Projektergebnisse

I was interested to understand the mechanism of action of widely used cancer drugs that bind to microtubules in patients. For many decades, we thought that these drugs contribute to cancer treatment by killing cancer cells during cell division. But, disappointingly, new, cell division specific drug candidates that were developed more recently largely failed as cancer drugs. This suggests that the hypothesis that killing dividing cells is sufficient to successfully kill a tumor is wrong. To understand if microtubule binding drugs have effects on mitotic cells that are independent of cell division, together with members from two partner laboratories, I developed the technology to observe cancer drug effects on the cell cycle in living tumors in mice over up to eight days after drug application. The technical setup combines confocal and 2 photon microscopy (in collaboration with the lab of Ralph Weissleder, MGH, Boston) with automated image analysis in 3 dimensions (in collaboration with the lab of Gaudenz Danuser, UTSouthwestern, Dallas). Using this technology, we found indirect evidence pointing towards division independent effects of microtubule binding drugs. These results are important for future improvements of cancer chemotherapy. The technology developed in this project was also published and will be useful for the study of other biological phenomena in living tissues in three dimensions.

Projektbezogene Publikationen (Auswahl)

• Differential determinants of cancer cell insensitivity to antimitotic drugs discriminated by a one-step cell imaging assay.
 Journal of Biomolecular Screening 18, 1062-1071 (2013)
  TangY, XieT, Florian S, Moerke N, Shamu C, Benes C & Mitchison TJ.
  
• In vivo cell cycle profiling in xenograft tumors by quantitative intravital microscopy. Nature Methods 12, 577–585 (2015)
  Chittajallu DR, Florian S, Kohler RH, Iwamoto Y, Orth JD,Weissleder R, Danuser G & Mitchison TJ
  
• Anti-microtubule drugs. (2016). In: Chang P., Ohi R. (eds) The Mitotic Spindle. Methods in Molecular Biology, vol 1413. Humana Press, New York, NY, pp 403-421 ISBN 978-1-4939-3540-6
  Florian S & Mitchison TJ