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Clin Cancer Res. 2013 Nov 1;19(21):5972-83. doi: 10.1158/1078-0432.CCR-13-1485. Epub 2013 Aug 29.

Nab-paclitaxel is an active drug in preclinical model of pediatric solid tumors.

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  • 1Authors' Affiliations: New Agent and Innovative Therapy Program; Department of Paediatric Laboratory Medicine; Division of Hematology and Oncology, Department of Paediatrics, The Hospital for Sick Children; and Institute of Medical Sciences, University of Toronto, Toronto, Canada.

Abstract

PURPOSE:

To investigate the antitumor effect of nab-paclitaxel, an albumin-stabilized nanoparticle formulation of paclitaxel, on pediatric solid tumor models.

EXPERIMENTAL DESIGN:

A panel of three rhabdomyosarcoma, one osteosarcoma and seven neuroblastoma cell lines were exposed to increasing concentrations of nab-paclitaxel in vitro. Cell viability was evaluated using the Alamar Blue Assay. Antitumor effect was further assessed in vivo in NOD/SCID xenograft and metastatic neuroblastoma mouse models. Tumor sections were analyzed by immunohistochemistry for cleaved caspase-3 and phospho-histone H3. Plasma and intratumoral paclitaxel concentrations were measured by liquid chromatography-mass spectrometry. Ratio of intratumoral and plasma concentration was compared between nab-paclitaxel and paclitaxel treatment groups.

RESULTS:

Nab-paclitaxel displayed significant cytotoxicity against most pediatric solid tumor cell lines in vitro in a dose-dependent manner. In vivo, nab-paclitaxel showed antitumor activity in both rhabdomyosarcoma (RH4 and RD) and neuroblastoma [SK-N-BE(2) and CHLA-20] xenograft models. In the SK-N-BE(2) metastatic model, nab-paclitaxel treatment significantly extended animal survival compared with control (P < 0.01). Nab-paclitaxel treatment induced tumor cell-cycle arrest and apoptosis in vivo. In the RH4 model, increased local relapse-free intervals were observed with nab-paclitaxel treatment (37.7 ± 3.2 days) comparing with paclitaxel (13.6 ± 2.07 days). Local relapsed tumors following paclitaxel treatment proved to be paclitaxel-resistant and remained responsive to nab-paclitaxel. Mechanistically, a higher tumor/plasma paclitaxel drug ratio in favor of nab-paclitaxel was observed.

CONCLUSIONS:

Nab-paclitaxel showed significant antitumor activity against all pediatric solid tumors associated with an enhanced drug intratumor delivery. Furthermore, testing of nab-paclitaxel in pediatric solid-tumor patient population is under development.

PMID:
23989978
[PubMed - indexed for MEDLINE]
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