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Potential Antagonism of Tubulin-Binding Anticancer Agents in Combination Therapies

Authors' Affiliations: ¹ Laboratory of Biology and Treatment of Metastasis, Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo Italy; ² Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milano Italy; and ³ AstraZeneca, Alderley Park, Macclesfield, United Kingdom

Requests for reprints: Raffaella Giavazzi, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: 39-035-319888; Fax: 39-035-319331; E-mail: giavazzi{at}marionegri.it.

ZD6126 is a vascular targeting agent, developed for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into the tubulin-binding agent N-acetylcolchinol. We have previously reported that in vitro N-acetylcolchinol disrupts microtubules and induces rapid changes in endothelial cell morphology, which in a tumor would lead to a rapid loss of tumor vessel integrity and subsequent extensive tumor necrosis. The aim of this study was to investigate the effect of cytotoxic antineoplastic drugs—cisplatin, doxorubicin, vincristine, paclitaxel, and docetaxel—on endothelial cell response to N-acetylcolchinol. We found that cisplatin and doxorubicin did not interfere with the ability of N-acetylcolchinol to cause morphologic changes in human umbilical vein endothelial cells, whereas vincristine showed additive effects. In contrast, the microtubule-stabilizing agents paclitaxel (1-10 µmol/L) and docetaxel (0.1-1 µmol/L) prevented the morphologic changes induced by N-acetylcolchinol in human umbilical vein endothelial cells. The effect was observed when cells were exposed to paclitaxel and N-acetylcolchinol together or when paclitaxel was given shortly before N-acetylcolchinol. Paclitaxel and N-acetylcolchinol interacted at the level of microtubule organization, as shown in immunofluorescence analysis of the cytoskeleton. The protective effect was reversible because 4 hours after paclitaxel wash out, cells recovered the sensitivity to N-acetylcolchinol. In vivo, pretreatment of mice with paclitaxel inhibited the vascular targeting activity of ZD6126 on newly formed vessels in the Matrigel plug assay and ZD6126-induced necrosis in tumors. These findings indicate that paclitaxel, depending on the timing and schedule of administration, can affect the vascular targeting activity of ZD6126, which may have an effect on the optimal scheduling of therapies based on the combined use of microtubule-stabilizing and microtubule-destabilizing agents.

Key Words: Vascular targeting • microtubule inhibitors • ZD6126 • paclitaxel • combination therapy