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.

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.

• 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)
• Copyright: Copyright 2009 Wiley-Liss, Inc.

Chemical References

• ABT751
• Sulfonamides
• Tubulin
• Tubulin Modulators

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)