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

Riferimento: 
Cancer Chemother Pharmacol. 2011 Dec;68(6):1469-75.
Autori: 
) Norris RE, Minturn JE, Brodeur GM, Maris JM, Adamson PC. norrisr@email.chop.edu
Fonte: 
Cancer Chemother Pharmacol. 2011 Dec;68(6):1469-75.
Anno: 
2011
Azione: 
La combinazione del retinoide isotretinoina (13cRA) e lestaurtinib (CEP-701) è sinergica in linee cellulari di neuroblastoma, suggerendo che questi agenti possono essere potenzialmente usati insieme dopo chemioterapia intensiva nei bambini con neuroblastoma ad alto rischio.
Target: 
13cRA – CEP-701/neuroblastoma infantile.

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) IC(50) 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 IC(50) 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 ED(50) 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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