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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1951-1961. Prepublished online as a Blood First Edition Paper on November 16, 2007; DOI 10.1182/blood-2007-05-089219. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-05-089219v1 111/4/1951    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Petit, I. Articles by Rafii, S. Search for Related Content PubMed PubMed Citation Articles by Petit, I. Articles by Rafii, S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The microtubule-targeting agent CA4P regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death Isabelle Petit1, Matthias A. Karajannis1, Loic Vincent1, Lauren Young1, Jason Butler1, Andrea T. Hooper1, Koji Shido1, Hermann Steller2, David J. Chaplin3, Eric Feldman1, and Shahin Rafii1 1 Howard Hughes Medical Institute, Ansary Center for Stem Cell Therapeutics, Department of Genetic Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY; 2 Howard Hughes Medical Institute, Strang Laboratory of Cancer Research, The Rockefeller University, New York, NY; and 3 OXiGENE, Waltham, MA Adhesion of leukemic cells to vascular cells may confer resistance to chemotherapeutic agents. We hypothesized that disruption of leukemic cell cytoskeletal stability and interference with vascular cell interactions would promote leukemic cell death. We demonstrate that low and nontoxic doses of microtubule-destabilizing agent combretastatin-A4-phosphate (CA4P) inhibit leukemic cell proliferation in vitro and induce mitotic arrest and cell death. Treatment of acute myeloid leukemias (AMLs) with CA4P leads to disruption of mitochondrial membrane potential, release of proapoptotic mitochondrial membrane proteins, and DNA fragmentation, resulting in cell death in part through a caspase-dependent manner. Furthermore, CA4P increases intracellular reactive oxygen species (ROS), and antioxidant treatment imparts partial protection from cell death, suggesting that ROS accumulation contributes to CA4P-induced cytotoxicity in AML. In vivo, CA4P inhibited proliferation and circulation of leukemic cells and diminished the extent of perivascular leukemic infiltrates, prolonging survival of mice that underwent xenotransplantation without inducing hematologic toxicity. CA4P decreases the interaction of leukemic cells with neovessels by down-regulating the expression of the adhesion molecule VCAM-1 thereby augmenting leukemic cell death. These data suggest that CA4P targets both circulating and vascular-adherent leukemic cells through mitochondrial damage and down-regulation of VCAM-1 without incurring hematologic toxicities. As such, CA4P provides for an effective means to treat refractory organ-infiltrating leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Shaked, T. Tang, J. Woloszynek, L. G. Daenen, S. Man, P. Xu, S.-R. Cai, J. M. Arbeit, E. E. Voest, D. J. Chaplin, et al. Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents Cancer Res., October 1, 2009; 69(19): 7524 - 7528. [Abstract] [Full Text] [PDF] G. M. Tozer, V. E. Prise, G. Lewis, S. Xie, I. Wilson, and S. A. Hill Nitric Oxide Synthase Inhibition Enhances the Tumor Vascular-Damaging Effects of Combretastatin A-4 3-O-Phosphate at Clinically Relevant Doses Clin. Cancer Res., June 1, 2009; 15(11): 3781 - 3790. [Abstract] [Full Text] [PDF]

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