Sakurai Fuminori, Terada Takeshi, Maruyama Masato, Watanabe Yoshihiko, Yamashita Fumiyoshi, Takakura Yoshinobu, Hashida Mitsuru
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Cancer Gene Ther. 2003 Sep;10(9):661-8. doi: 10.1038/sj.cgt.7700617.
We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-beta or IFN-gamma, 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)-alpha and IFN-gamma, while injection of lipoplexes containing pI:pC led to a low level of TNF-alpha and undetectable IFN-gamma 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-alpha and IFN-gamma 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-beta induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-beta 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-beta antibody treatment, indicating that IFN-beta produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-beta in the lung delivered by intravenous administration of lipoplex containing IFN-beta gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.
我们评估并比较了含有编码IFN-β或IFN-γ的质粒的脂质体配方以及合成双链RNA聚肌苷酸:聚胞苷酸（pI:pC，一种I型干扰素诱导剂）经全身给药在肺癌转移模型中的疗效，该模型通过将结肠癌CT-26细胞静脉注射到免疫相容性小鼠体内构建。无论是否插入IFN基因，注射含质粒DNA的脂质体都会刺激促炎细胞因子如肿瘤坏死因子（TNF）-α和IFN-γ的血清浓度短暂升高，而注射含pI:pC的脂质体则导致低水平的TNF-α产生且未检测到IFN-γ生成。此外，注射这些含质粒的脂质体可在肺组织培养物中产生I型和II型干扰素的混合物，部分源自插入的IFN基因。在肿瘤预防实验中，无论是否插入IFN基因，静脉注射含质粒的脂质体均显示肺转移结节显著减少，这可能是由于质粒中的CpG基序非特异性诱导的TNF-α和IFN-γ等促炎细胞因子以及产生的I型干扰素所致。另一方面，pI:pC-脂质体的抗转移作用似乎主要归因于pI:pC诱导的IFN-β。在已建立的肺转移实验中，单次静脉注射含IFN-β基因或pI:pC的脂质体（而非其他脂质体）对肿瘤转移显示出显著的治疗效果：肿瘤结节减少且荷瘤小鼠存活时间延长。抗IFN-β抗体处理特异性削弱了治疗效果，表明脂质体产生的IFN-β在抑制已建立的转移性肺肿瘤中起重要作用。因此，通过静脉注射含IFN-β基因或pI:pC的脂质体递送肺部局部IFN-β可能是抑制已建立的转移性肺肿瘤的一种方便且有用的方法。
