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Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone

¹ Bayer Schering Pharma AG, TRG Oncology; ² Charité, Institute of Pathology, Humboldt University; and ³ Institute for Chemistry and Biochemistry, Freie Universität, Berlin, Germany; ⁴ Institut National de la Sante et de la Recherche Medicale, U848; ⁵ Institut Gustave Roussy; and ⁶ Université Paris-Sud 11, Villejuif, France

Requests for reprints: Jens Hoffmann, Bayer Schering Pharma AG, TRG Oncology, Müllerstrasse, 172-178, G-13342 Berlin, Germany. Phone: 49-30-468-17611; Fax: 49-30-468-97611; E-mail: jens.hoffmann{at}bayerhealthcare.com or Guido Kroemer, Institut National de la Sante et de la Recherche Medicale, U848, Institut Gustave Roussy, Pavillon de Recherche 139 rue Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-4211-6046; Fax: 33-1-4211-6047; E-mail: kroemer{at}igr.fr.

Key Words: apoptosis • Bcl-2 • MDR • microtubules • mitotic catastrophe

Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulin-polymerizing) agents. Cellular uptake and fractionation/localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-X_L, or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program. [Cancer Res 2008;68(13):5301–8]

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