Microtubule targeting antimitotic drugs induce a lower mitotic arrest than clinically less effective antimitotic Eg5 inhibitors in mouse xenografts.

Despite immense progress in targeted cancer drug design, to date, the most important drugs in chemotherapy remain traditional cytotoxic drugs which are thought to kill proliferating cells, no matter if malignant of not. This hypothesis is based on results from the 1970s coming from mouse leukemia models or cell culture experiments. Microtubule binding drugs are clinically important antiproliferative drugs which arrest cultured cancer cells in mitosis. As opposed to empirically found microtubule binding drugs, newer drugs designed from scratch to induce mitotic arrest have repeatedly failed in clinical trials, suggesting that the antitumor effect of microtubule binding drugs is still not well understood. Alas, tissue culture assays are not predictive of their respective clinical success, suggesting that more realistic models are needed to understand why there are such huge differences in antitumor efficacy. Therefore, in this project, we used in vivo microscopy of mouse xenografts to compare the cell cycle effects of microtubule drugs to those of newer, targeted antimitotic drugs in the form of inhibitors of the mitotic kinesin Eg5. Image analysis with a custom developed software for automated three dimensional segmentation and cell cycle classification revealed that the microtubule interacting drugs Paclitaxel and Eribulin which are in wide clinical use induce a much lower mitotic arrest than the Eg5 inhibitor Ispinesib which failed clinical trials. This suggests that, rather than mitotic arrest, a different mechanism, intrinsically coupled to microtubule binding, might be essential for the antitumor effect of microtubule drugs in vivo. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A297. Citation Format: Stefan Florian, Deepak R. Chittajallu, Rainer H. Kohler, James D. Orth, Peter K. Sorger, Ralph Weissleder, Gaudenz Danuser, Timothy J. Mitchison. Microtubule targeting antimitotic drugs induce a lower mitotic arrest than clinically less effective antimitotic Eg5 inhibitors in mouse xenografts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A297.