title: Nab-paclitaxel is an active drug in preclinical model of pediatric solid tumors.
abstract: OBJECTIVE
  To investigate the antitumor effect of nab-paclitaxel, an albumin-stabilized nanoparticle formulation of paclitaxel, on pediatric solid tumor models.
  
  
  METHODS
  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.
authors.affiliation: Authors' 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.
authors.forename: Libo
authors.initials: L
authors.lastname: Zhang
authors.forename: Paula
authors.initials: P
authors.lastname: Marrano
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.forename: Michael
authors.initials: M
authors.lastname: Leadley
authors.forename: Evelyn
authors.initials: E
authors.lastname: Elias
authors.forename: Paul
authors.initials: P
authors.lastname: Thorner
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
mesh_terms: D000418:Albumins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel