Abstract | BACKGROUND:
ABT-751, an orally bioavailable sulfonamide, binds beta-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 IC(50) 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.
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Authors | Holly J Meany, Dan L Sackett, John M Maris, Yvona Ward, Andrew Krivoshik, Susan L Cohn, Seth M Steinberg, Frank M Balis, Elizabeth Fox |
Journal | Pediatric blood & cancer
(Pediatr Blood Cancer)
Vol. 54
Issue 1
Pg. 47-54
(Jan 2010)
ISSN: 1545-5017 [Electronic] United States |
PMID | 19731320
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Copyright | Copyright 2009 Wiley-Liss, Inc. |
Chemical References |
- ABT751
- Sulfonamides
- Tubulin
- Tubulin Modulators
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Topics |
- Adolescent
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Child
- Child, Preschool
- Disease-Free Survival
- Female
- Humans
- In Vitro Techniques
- Male
- Neoplasm Recurrence, Local
(drug therapy)
- Neuroblastoma
(drug therapy, pathology)
- Pilot Projects
- Prognosis
- Sulfonamides
(pharmacology, therapeutic use)
- Survival Rate
- Treatment Outcome
- Tubulin
(metabolism)
- Tubulin Modulators
(pharmacology, therapeutic use)
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