This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Micheletti, G. Articles by Giavazzi, R. Search for Related Content PubMed PubMed Citation Articles by Micheletti, G. Articles by Giavazzi, R.

Vascular-targeting Activity of ZD6126, a Novel Tubulin-binding Agent¹

Laboratory of Biology and Therapy of Metastasis, Department of Oncology, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy

The tubulin-binding agent ZD6126 is a novel vascular-targeting agent in clinical development for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into N-acetylcolchinol (ZD6126 phenol). In this study, we have explored the antivascular property of N-acetylcolchinol in vitro and ZD6126 in vivo. In cell culture, N-acetylcolchinol induced rapid changes in the morphology of human umbilical vein and lung microvessel endothelial cells. Within 40 min, the compound induced endothelial cell contraction, destabilization of the tubulin cytoskeleton, induction of actin stress fibers, and membrane blebbing. These effects occurred at noncytotoxic concentrations and were rapidly reversed on removal of the drug. Nonconfluent endothelial cells were more sensitive than confluent, quiescent cells. Among different cell types, endothelial cells were the most sensitive to the induction of morphological changes, whereas smooth muscle cells were not affected. In vitro, N-acetylcolchinol rapidly disrupted a network of newly formed cords. In vivo, ZD6126 caused shut down of newly formed vessels in the Matrigel plug assay, shortly after injection. This study indicates that rapid alteration of endothelial cell morphology may be responsible for the loss of tumor blood vessel integrity, vessel shut down, and extensive tumor necrosis induced by ZD6126 in experimental tumor models.

This article has been cited by other articles:

				E. L. Schwartz Antivascular Actions of Microtubule-Binding Drugs Clin. Cancer Res., April 15, 2009; 15(8): 2594 - 2601. [Abstract] [Full Text] [PDF]

				J. D. Mocanu, K. W. Yip, J. Skliarenko, W. Shi, P. Busson, K.-W. Lo, C. Bastianutto, and F.-F. Liu Imaging and Modulating Antisense Microdistribution in Solid Human Xenograft Tumor Models Clin. Cancer Res., October 1, 2007; 13(19): 5935 - 5941. [Abstract] [Full Text] [PDF]

				J. Gamrekelashvili, C. Kruger, R. von Wasielewski, M. Hoffmann, K. M. Huster, D. H. Busch, M. P. Manns, F. Korangy, and T. F. Greten Necrotic Tumor Cell Death In Vivo Impairs Tumor-Specific Immune Responses J. Immunol., February 1, 2007; 178(3): 1573 - 1580. [Abstract] [Full Text] [PDF]

				L. V. Beerepoot, S. A. Radema, E. O. Witteveen, T. Thomas, C. Wheeler, S. Kempin, and E. E. Voest Phase I Clinical Evaluation of Weekly Administration of the Novel Vascular-Targeting Agent, ZD6126, in Patients With Solid Tumors J. Clin. Oncol., April 1, 2006; 24(10): 1491 - 1498. [Abstract] [Full Text] [PDF]

				J. V. Skliarenko, S. J. Lunt, M. L. Gordon, A. Vitkin, M. Milosevic, and R. P. Hill Effects of the Vascular Disrupting Agent ZD6126 on Interstitial Fluid Pressure and Cell Survival in Tumors Cancer Res., February 15, 2006; 66(4): 2074 - 2080. [Abstract] [Full Text] [PDF]

				V. K.W. Wong, P. Chiu, S. S.M. Chung, L. M.C. Chow, Y.-Z. Zhao, B. B. Yang, and B. C.B. Ko Pseudolaric Acid B, a Novel Microtubule-Destabilizing Agent That Circumvents Multidrug Resistance Phenotype and Exhibits Antitumor Activity In vivo Clin. Cancer Res., August 15, 2005; 11(16): 6002 - 6011. [Abstract] [Full Text] [PDF]

				G. Taraboletti, G. Micheletti, R. Dossi, P. Borsotti, M. Martinelli, F. Fiordaliso, A. J. Ryan, and R. Giavazzi Potential Antagonism of Tubulin-Binding Anticancer Agents in Combination Therapies Clin. Cancer Res., April 1, 2005; 11(7): 2720 - 2726. [Abstract] [Full Text] [PDF]

				P. R. Wachsberger, R. Burd, N. Marero, C. Daskalakis, A. Ryan, P. McCue, and A. P. Dicker Effect of the Tumor Vascular-Damaging Agent, ZD6126, on the Radioresponse of U87 Glioblastoma Clin. Cancer Res., January 15, 2005; 11(2): 835 - 842. [Abstract] [Full Text] [PDF]

				S. Kasibhatla, H. Gourdeau, K. Meerovitch, J. Drewe, S. Reddy, L. Qiu, H. Zhang, F. Bergeron, D. Bouffard, Q. Yang, et al. Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity Mol. Cancer Ther., November 1, 2004; 3(11): 1365 - 1374. [Abstract] [Full Text] [PDF]

				H. Gourdeau, L. Leblond, B. Hamelin, C. Desputeau, K. Dong, I. Kianicka, D. Custeau, C. Boudreau, L. Geerts, S.-X. Cai, et al. Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents Mol. Cancer Ther., November 1, 2004; 3(11): 1375 - 1384. [Abstract] [Full Text] [PDF]

				J. L. Evelhoch, P. M. LoRusso, Z. He, Z. DelProposto, L. Polin, T. H. Corbett, P. Langmuir, C. Wheeler, A. Stone, J. Leadbetter, et al. Magnetic Resonance Imaging Measurements of the Response of Murine and Human Tumors to the Vascular-Targeting Agent ZD6126 Clin. Cancer Res., June 1, 2004; 10(11): 3650 - 3657. [Abstract] [Full Text] [PDF]

				A R Padhani MRI for assessing antivascular cancer treatments Br. J. Radiol., December 1, 2003; 76(suppl_1): S60 - S80. [Abstract] [Full Text] [PDF]