RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Tanno, B  Mancini, C  Vitali, R  Mancuso, M  McDowell, HP  Dominici, C  Raschella, G 
Citation: Tanno B, etal., Clin Cancer Res. 2006 Nov 15;12(22):6772-80.
RGD ID: 7242922
Pubmed: PMID:17121898   (View Abstract at PubMed)
DOI: DOI:10.1158/1078-0432.CCR-06-1479   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
neuroblastoma  IMP 7242922protein: decreased tyrosine phosphorylation: : Y1131RGD 
neuroblastoma  ISOIGF1R (Homo sapiens)7242922; 7242922protein: decreased tyrosine phosphorylation: : Y1131RGD 

Objects Annotated

Genes (Rattus norvegicus)
Igf1r  (insulin-like growth factor 1 receptor)

Genes (Mus musculus)
Igf1r  (insulin-like growth factor I receptor)

Genes (Homo sapiens)
IGF1R  (insulin like growth factor 1 receptor)


Additional Information