title: Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer.
abstract: OBJECTIVE
  The RNA interference effect is an alternative to antisense DNA as an experimental method of down-regulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101.
  
  
  METHODS
  In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor.
  
  
  RESULTS
  The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer.
  
  
  CONCLUSIONS
  By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co, Ltd., Kyoto, Japan; and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. j.yano@po.nippon-shinkayu.co.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Yano
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Nogawa
authors.forename: Isao
authors.initials: I
authors.lastname: Kashimori
authors.forename: Haruna
authors.initials: H
authors.lastname: Naito
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ishiyama
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Ohgi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002412:Cations / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009841:Oligonucleotides / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D008081:Liposomes; D009841:Oligonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D004247:DNA