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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

TitoloDown-regulation of insulin-like growth factor I receptor activity by NVP-AEW541 has an antitumor effect on neuroblastoma cells in vitro and in vivo
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2006
AutoriTanno, Barbara, Mancini C., Vitali Roberta, Mancuso Mariateresa, McDowell H.P., Dominici C., and Raschellà G.
RivistaClinical Cancer Research
Volume12
Paginazione6772-6780
ISSN10780432
Parole chiaveAdrenal Gland Neoplasms, animal experiment, animal model, animal tissue, Animals, antineoplastic activity, antineoplastic agent, Antineoplastic Agents, Apoptosis, article, Brain Neoplasms, cancer growth, cancer inhibition, cancer invasion, cell proliferation, combined immunodeficiency, concentration response, controlled study, Cultured, Down-Regulation, drug mechanism, Heterologous, human, human cell, human tissue, Humans, IGF Type 1, in vitro study, in vivo study, Kidney Neoplasms, male, messenger RNA, Mice, microvascularization, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, mouse, Neoplasm Invasiveness, Neuroblastoma, neuroblastoma cell, nonhuman, Nude, nvp aew 541, Phosphorylation, priority journal, protein expression, protein kinase B, Proto-Oncogene Proteins c-akt, pyrimidine derivative, Pyrimidines, Pyrroles, real time polymerase chain reaction, Receptor, receptor down regulation, recombinant somatomedin B, single drug dose, somatomedin C receptor, transplantation, Tumor Burden, Tumor Cells, tumor xenograft, vasculotropin, Xenograft Model Antitumor Assays
Abstract

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 endothetial 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. © 2006 American Association for Cancer Research.

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URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-33845313289&doi=10.1158%2f1078-0432.CCR-06-1479&partnerID=40&md5=0ef5d793acd2bf7d720e9e2f4bb92529
DOI10.1158/1078-0432.CCR-06-1479
Citation KeyTanno20066772