title: Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma.
abstract: The development of effective, systemic therapies for metastatic cancer is highly desired. We show here that the systemic delivery of sequence-specific small interfering RNA (siRNA) against the EWS-FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. The nonviral delivery system uses a cyclodextrin-containing polycation to bind and protect siRNA and transferrin as a targeting ligand for delivery to transferrin receptor-expressing tumor cells. Removal of the targeting ligand or the use of a control siRNA sequence eliminates the antitumor effects. Additionally, no abnormalities in interleukin-12 and IFN-alpha, liver and kidney function tests, complete blood counts, or pathology of major organs are observed from long-term, low-pressure, low-volume tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted, nonviral siRNA delivery system.
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Siwen
authors.initials: S
authors.lastname: Hu-Lieskovan
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Heidel
authors.forename: Derek W
authors.initials: DW
authors.lastname: Bartlett
authors.forename: Mark E
authors.initials: ME
authors.lastname: Davis
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics* / Q000633:toxicity; D034802:RNA-Binding Protein EWS; D011990:Receptors, Transferrin / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014161:Transduction, Genetic
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; D011990:Receptors, Transferrin; D008156:Luciferases