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.
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.


METHODS
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.
Meany
Holly J
HJ
Department of Hematology/Oncology, Children's National Medical Center, Washington, DC 20010, USA. hmeany@cnmc.org
Sackett
Dan L
DL
Maris
John M
JM
Ward
Yvona
Y
Krivoshik
Andrew
A
Cohn
Susan L
SL
Steinberg
Seth M
SM
Balis
Frank M
FM
Fox
Elizabeth
E
D000293:Adolescent; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010865:Pilot Projects; D011379:Prognosis; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use*
C490492:ABT751; D013449:Sulfonamides; D014404:Tubulin; D050257:Tubulin Modulators