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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2011

01-12-2011 | Original Article

Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma

Authors: Robin E. Norris, Jane E. Minturn, Garrett M. Brodeur, John M. Maris, Peter C. Adamson

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2011

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Abstract

Purpose

Lestaurtinib (CEP-701), a multi-kinase inhibitor with potent activity against the Trk family of receptor tyrosine kinases, has undergone early phase clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with isotretinoin (13cRA) and fenretinide (4HPR), two retinoids that have been studied in children with high-risk neuroblastoma.

Methods

In vitro growth inhibition was assessed following a 72-hour drug exposure using the sulforhodamine B (SRB) assay in eight neuroblastoma cell lines with variable TrkB expression. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701.

Results

The median (range) IC50 of single-agent CEP-701 across all cell lines was 0.09 (0.08–0.3) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in four of the five cell lines studied. Addition of 1 or 5 μM of 13cRA decreased the median (range) CEP-701 IC50 1.5-fold (1.1–2.8-fold) and 1.7-fold (1.5–1.8-fold), respectively. With 10 μM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED50 of 1.3 (1.1–1.5).

Conclusions

The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be potentially studied together in the setting of minimal residual disease following intensive chemoradiotherapy for children with high-risk neuroblastoma.
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Metadata
Title
Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma
Authors
Robin E. Norris
Jane E. Minturn
Garrett M. Brodeur
John M. Maris
Peter C. Adamson
Publication date
01-12-2011
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-011-1623-y

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