Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I: Poly C in a murine lung metastasis model

Fuminori Sakurai, Takeshi Terada, Masato Maruyama, Yoshihiko Watanabe, Fumiyoshi Yamashita, Yoshinobu Takakura, Mitsuru Hashida

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-β or IFN-γ, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IFN-γ, while injection of lipoplexes containing pI:pC led to a low level of TNF-α and undetectable IFN-γ production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-α and IFN-γ nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-β induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-β gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-β antibody treatment, indicating that IFN-γ produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-β in the lung delivered by intravenous administration of lipoplex containing IFN-β gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.

Original languageEnglish
Pages (from-to)661-668
Number of pages8
JournalCancer Gene Therapy
Volume10
Issue number9
DOIs
Publication statusPublished - Sep 1 2003
Externally publishedYes

Fingerprint

Poly C
Poly I-C
Therapeutic Uses
Interferons
Neoplasm Metastasis
Lung
Plasmids
Genes
Tumor Necrosis Factor-alpha
Insertional Mutagenesis
Neoplasms
Intravenous Administration
Injections
Cytokines
Tumor Burden
Intravenous Injections
Anti-Idiotypic Antibodies
Colon
RNA
Carcinoma

Keywords

  • Interferon-β
  • Lipoplex
  • Lung metastasis
  • Poly C
  • Poly I

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I : Poly C in a murine lung metastasis model. / Sakurai, Fuminori; Terada, Takeshi; Maruyama, Masato; Watanabe, Yoshihiko; Yamashita, Fumiyoshi; Takakura, Yoshinobu; Hashida, Mitsuru.

In: Cancer Gene Therapy, Vol. 10, No. 9, 01.09.2003, p. 661-668.

Research output: Contribution to journalArticle

Sakurai, Fuminori ; Terada, Takeshi ; Maruyama, Masato ; Watanabe, Yoshihiko ; Yamashita, Fumiyoshi ; Takakura, Yoshinobu ; Hashida, Mitsuru. / Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I : Poly C in a murine lung metastasis model. In: Cancer Gene Therapy. 2003 ; Vol. 10, No. 9. pp. 661-668.
@article{30a4b52f47634a8fb53a54f7d19850bd,
title = "Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I: Poly C in a murine lung metastasis model",
abstract = "We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-β or IFN-γ, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IFN-γ, while injection of lipoplexes containing pI:pC led to a low level of TNF-α and undetectable IFN-γ production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-α and IFN-γ nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-β induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-β gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-β antibody treatment, indicating that IFN-γ produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-β in the lung delivered by intravenous administration of lipoplex containing IFN-β gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.",
keywords = "Interferon-β, Lipoplex, Lung metastasis, Poly C, Poly I",
author = "Fuminori Sakurai and Takeshi Terada and Masato Maruyama and Yoshihiko Watanabe and Fumiyoshi Yamashita and Yoshinobu Takakura and Mitsuru Hashida",
year = "2003",
month = "9",
day = "1",
doi = "10.1038/sj.cgt.7700617",
language = "English",
volume = "10",
pages = "661--668",
journal = "Cancer Gene Therapy",
issn = "0929-1903",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I

T2 - Poly C in a murine lung metastasis model

AU - Sakurai, Fuminori

AU - Terada, Takeshi

AU - Maruyama, Masato

AU - Watanabe, Yoshihiko

AU - Yamashita, Fumiyoshi

AU - Takakura, Yoshinobu

AU - Hashida, Mitsuru

PY - 2003/9/1

Y1 - 2003/9/1

N2 - We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-β or IFN-γ, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IFN-γ, while injection of lipoplexes containing pI:pC led to a low level of TNF-α and undetectable IFN-γ production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-α and IFN-γ nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-β induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-β gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-β antibody treatment, indicating that IFN-γ produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-β in the lung delivered by intravenous administration of lipoplex containing IFN-β gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.

AB - We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-β or IFN-γ, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IFN-γ, while injection of lipoplexes containing pI:pC led to a low level of TNF-α and undetectable IFN-γ production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-α and IFN-γ nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-β induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-β gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-β antibody treatment, indicating that IFN-γ produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-β in the lung delivered by intravenous administration of lipoplex containing IFN-β gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.

KW - Interferon-β

KW - Lipoplex

KW - Lung metastasis

KW - Poly C

KW - Poly I

UR - http://www.scopus.com/inward/record.url?scp=0141676278&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0141676278&partnerID=8YFLogxK

U2 - 10.1038/sj.cgt.7700617

DO - 10.1038/sj.cgt.7700617

M3 - Article

C2 - 12944985

AN - SCOPUS:0141676278

VL - 10

SP - 661

EP - 668

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 9

ER -