Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction
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Janine Stucke-Ring1,*, Julian Ronnacker1,*, Caroline Brand1, Carsten Höltke2, Christoph Schliemann1, Torsten Kessler1, Lars Henning Schmidt1, Saliha Harrach1, Verena Mantke1, Heike Hintelmann1, Wolfgang Hartmann3, Eva Wardelmann3, Georg Lenz1, Bernhard Wünsch4, Carsten Müller-Tidow5, Rolf M. Mesters1, Christian Schwöppe1,#, Wolfgang E. Berdel1,#
1Department of Medicine A (Hematology, Hemostaseology, Oncology and Pneumology), University Hospital of Muenster, Muenster, Germany
2Department of Clinical Radiology, University Hospital of Muenster, Muenster, Germany
3Gerhard-Domagk Institute for Pathology, University Hospital of Muenster, Muenster, Germany
4Department of Pharmaceutical Chemistry, Westfalian Wilhelms-University, Muenster, Germany
5Department of Hematology and Oncology, University Hospital Halle, Halle, Germany
*These authors have contributed equally and share first authorship
Wolfgang E. Berdel, email: email@example.com
Keywords: retargeted tissue factor, vascular targeting, vascular infarction, doxorubicin tumor entrapment
Received: August 16, 2016 Accepted: October 04, 2016 Published: October 11, 2016
Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells.
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