title: The impact of retinoic acid treatment on the sensitivity of neuroblastoma             cells to fenretinide.
abstract: Despite the successful introduction of 13-cis retinoic acid (13cisRA) therapy             for the treatment of neuroblastoma, approximately 50% patients do not respond             or experience relapse. A retinoid analogue, fenretinide [N-(4-hydroxyphenyl) retinamide;             4-HPR] can induce apoptosis in neuroblastoma cell lines and could have clinical             use after therapy with 13cisRA. However, there are important questions concerning             potential retinoid drug interactions which need to be addressed. The aim of this             study was to investigate the influence of retinoic acid pre-treatment on fenretinide-induced             apoptosis and fenretinide metabolism in neuroblastoma cell lines. Apoptosis was             measured by flow cytometry of propidium iodide-stained neuroblastoma cells and             a live-cell imaging assay. Intracellular fenretinide metabolism was determined             by HPLC analysis. Pre-treatment of neuroblastoma cell lines with retinoic acid             (RA) resulted in a significant decrease in the apoptotic response to fenretinide             in three of the four lines tested. Comparison between responsive and non-responsive             cell lines suggested that RA sensitivity was required to promote fenretinide resistance,             and that this was mediated by up-regulation of Bcl-2 and the inhibition of pro-apoptotic             fenretinide signalling pathways. Induction of the oxidative metabolism of fenretinide             after RA pre-treatment did not significantly impact on intracellular parent drug             levels and is unlikely to explain the decreased apoptotic response observed. The             interaction between RA and fenretinide could have important implications for the             scheduling of fenretinide in therapeutic protocols for neuroblastoma.
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Armstrong
authors.forename: Shaun
authors.initials: S
authors.lastname: Martin
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Illingworth
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.forename: Abbie
authors.initials: A
authors.lastname: Neilson
authors.forename: Penny E
authors.initials: PE
authors.lastname: Lovat
authors.forename: Chris P F
authors.initials: CP
authors.lastname: Redfern
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D017313:Fenretinide / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017313:Fenretinide; D014212:Tretinoin