Antitumor Activity of Small Interfering RNA/Cationic Liposome Complex in Mouse Models of Cancer

• Published in: Clinical cancer research 2004-11, Vol.10 (22), p.7721-7726
• Main Authors: YANO, Junichi, HIRABAYASHI, Kazuko, IRIMURA, Tatsuro, NAKAGAWA, Shin-Ichiro, YAMAGUCHI, Tohru, NOGAWA, Masaki, KASHIMORI, Isao, NAITO, Haruna, KITAGAWA, Hidetoshi, ISHIYAMA, Kouichi, OHGI, Tadaaki
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Cations - chemistry; Cell Line, Tumor; Disease Models, Animal; DNA - chemistry; Dose-Response Relationship, Drug; Down-Regulation; Humans; Injections, Intravenous; Liposomes - chemistry; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - genetics; Oligonucleotides - chemistry; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - chemistry; RNA, Small Interfering - chemistry; RNA, Small Interfering - metabolism; Time Factors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-1049

Purpose: 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. Experimental Design: 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.