Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice.
Several lines of evidence now indicate that type 1 insulin-like growth factor receptor (IGF1R) function may be particularly important in the pathogenesis of the pediatric cancer neuroblastoma. Modulating the expression of specific genes involved in neuroblastoma tumorigenesis could provide a much needed alternative treatment strategy for poor prognosis disease. We now report construction of an antisense expression vector to the IGF1R that markedly reduces cellular IGF1R levels and inhibits the proliferation and clonogenicity of neuroblastoma cells in vitro but not that of IGF1R null cells. This antitumor activity is associated with the induction of apoptotic cell death in transfected cells, as measured by annexin V staining and flow cytometry. Direct injection of this vector into established tumors growing in syngeneic mice results in a marked inhibition of tumor growth with complete and durable tumor regression in one-half of the animals. This effect appears to be immunologically mediated in that vector injection of neuroblastoma tumors growing in severe combined immunodeficiency mice results in only modest delay of tumor growth. Our results suggest that inhibition of IGF1R expression by direct intratumoral delivery of an antisense construct could provide a novel therapeutic approach in the management of poor prognosis neuroblastoma.
Liu
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Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona, Tucson 85724, USA.
Turbyville
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T
Fritz
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Whitesell
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L
D000818:Animals; D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015552:Injections, Intralesional; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016372:RNA, Antisense / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D016375:Antisense Elements (Genetics); D018076:DNA, Complementary; D016372:RNA, Antisense; D017527:Receptor, IGF Type 2