This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanno, B. Articles by Raschellà, G. Search for Related Content PubMed PubMed Citation Articles by Tanno, B. Articles by Raschellà, G.

Down-Regulation of Insulin-Like Growth Factor I Receptor Activity by NVP-AEW541 Has an Antitumor Effect on Neuroblastoma Cells In vitro and In vivo

Authors' Affiliations: ¹ Section of Toxicology and Biomedical Sciences, Ente per le Nuove tecnologie l'Energia e l'Ambiente, Research Center Casaccia; ² La Sapienza University, Department of Pediatrics; ³ Laboratory of Oncology, Bambino Gesù Children's Hospital, Rome, Italy; ⁴ Royal Liverpool Children's NHS Trust Alder Hey, Department of Oncology, Liverpool, United Kingdom; and ⁵ School of Reproductive and Developmental Medicine, Division of Child Health, Liverpool University, Liverpool, United Kingdom

Requests for reprints: Giuseppe Raschellà, Section of Toxicology and Biomedical Sciences, ENEA Research Center Casaccia, Via Anguillarese, 301, 00060 Rome, Italy. Phone: 39-0630483172; Fax: 39-0630486559; E-mail: raschella{at}casaccia.enea.it.

Purpose: Signaling through insulin-like growth factor I receptor (IGF-IR) is important for growth and survival of many tumor types. Neuroblastoma is sensitive to IGF.

Experimental Design: We assessed the ability of NVP-AEW541, a recently developed small molecule that selectively inhibits IGF-IR activity, for neuroblastoma growth effects in vitro and in vivo. Our data showed that, in a panel of 10 neuroblastoma cell lines positive for IGF-IR expression, NVP-AEW541 inhibited in vitro proliferation in a submicromolar/micromolar (0.4-6.8) range of concentrations.

Results: As expected, NVP-AEW541 inhibited IGF-II–mediated stimulation of IGF-IR and Akt. In addition to growth inhibition, the drug also induced apoptosis in vitro. Oral administration of NVP-AEW541 (50 mg/kg twice daily) inhibited tumor growth of neuroblastoma xenografts in nude mice. Analysis of tumors from the drug-treated animals revealed a marked apoptotic pattern and a decrease in microvascularization compared with controls. Interestingly, quantitative real-time PCR detected both in vitro and in vivo a significant down-regulation of mRNA for vascular endothelial growth factor (VEGF) caused by NVP-AEW541. In addition, in Matrigel-coated chambers and in severe combined immunodeficient mice tail vein injected with neuroblastoma cells, tumor invasiveness was significantly reduced by this agent. Analysis of IGF-IR expression in a series of 43 neuroblastoma primary tumors revealed IGF-IR positivity in 86% of cases.

Conclusions: Taken together, these data indicate that NVP-AEW541 can be considered as a novel promising candidate for treatment of neuroblastoma patients.

This article has been cited by other articles:

				U. McDermott, A. J. Iafrate, N. S. Gray, T. Shioda, M. Classon, S. Maheswaran, W. Zhou, H. G. Choi, S. L. Smith, L. Dowell, et al. Genomic Alterations of Anaplastic Lymphoma Kinase May Sensitize Tumors to Anaplastic Lymphoma Kinase Inhibitors Cancer Res., May 1, 2008; 68(9): 3389 - 3395. [Abstract] [Full Text] [PDF]