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Clinical outcome in children with recurrent neuroblastoma treated with ABT-751 and effect of ABT-751 on proliferation of neuroblastoma cell lines and on tubulin polymerization in vitro

Authors

  • Holly J. Meany MD,

    Corresponding author
    1. Department of Hematology/Oncology, Children's National Medical Center, Washington, District of Columbia
    2. Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
    • Department of Hematology/Oncology, Children's National Medical Center, Michigan Avenue NW, Washington, DC 20010.
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  • Dan L. Sackett PhD,

    1. Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
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  • John M. Maris MD,

    1. Center for Childhood Cancer Research at The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Yvona Ward PhD,

    1. Cell and Cancer Biology Branch, Center for Cancer Research, NCI, Bethesda, Maryland
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  • Andrew Krivoshik MD, PhD,

    1. Abbott Laboratories, Abbott Park, Illinois
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  • Susan L. Cohn MD,

    1. University of Chicago Comer Children's Hospital, Chicago, Illinois
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  • Seth M. Steinberg PhD,

    1. Biostatistics and Data Management Section, Center for Cancer Research, NCI, Bethesda, Maryland
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  • Frank M. Balis MD,

    1. Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
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  • Elizabeth Fox MD

    1. Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
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  • Andrew Krivoshik, MD, PhD is employed by and has ownership interest in Abbott Laboratories. The other authors of this manuscript do not have conflicts of interest to disclose.

Abstract

Background

ABT-751, an orally bioavailable sulfonamide, binds β-tubulin to inhibit microtubule polymerization. We described response and event-free survival (EFS) in children with neuroblastoma and other solid tumors receiving ABT-751, assessed in vitro cytotoxicity of ABT-751 and evaluated the effect of ABT-751 on tubulin polymerization in peripheral blood mononuclear cells (PBMC) and pediatric tumor cell lines.

Procedure

Patients with neuroblastoma (n = 50) or other solid tumors (n = 26) enrolled on the ABT-751 pediatric phase I and pilot trials were reviewed. The sulforhodamine B (SRB) and ACEA Real-Time Cell Electronic Sensing (RT-CES) assays were used to determine the in vitro cytotoxicity. Pharmacodynamic effects on tubulin polymerization/depolymerization were assessed by Western blot and confocal microscopy using antibodies specific for post-translational modifications of polymerized tubulin.

Results

Forty-five patients with neuroblastoma were evaluated for anti-tumor response. No complete or partial responses were documented. The median EFS was 9.3 weeks for children with neuroblastoma and 3.3 weeks for children other solid tumors (P < 0.0001). The ABT-751 IC50 was 0.6–2.6 mcM in neuroblastoma and 0.7–4.6 mcM in other solid tumor cell lines. Following drug exposure, polymerized tubulin decreased in a concentration- and time-dependent manner in cell lines.

Conclusions

In children treated with ABT-751, the EFS is longer in children with neuroblastoma as compared to other diagnoses. In vitro, ABT-751 was cytotoxic at concentrations tolerable in children. Effects of ABT-751 on polymerization and microtubule structure were time- and dose-dependent but not dependent on tumor type. Pediatr Blood Cancer 2010; 54:47–54. © 2009 Wiley-Liss, Inc.

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