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Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice

Cancer Gene Therapy volume 17, pages 512–522 (2010)Cite this article

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Abstract

Interleukin 12 (IL-12) is a proinflammatory cytokine with antitumor activity. All-trans–retinoic acid (ATRA) exerts antitumor effects by regulating a variety of gene expressions, including tumor necrosis factor receptor 1 (TNFR1), increases the number of TNFR1 and potentiates TNF-α-induced apoptosis in cancer cells. In this study, ATRA-incorporated cationic liposome (ATRA-cationic liposome)/IL-12 plasmid DNA (pDNA) complexes were prepared to improve therapeutic efficacy of cationic liposome/IL-12 pDNA complexes in a mouse model of metastatic lung tumor after intravenous injection. IL-12 production in lungs by ATRA-cationic liposome/IL-12 pDNA complexes was comparable with that by cationic liposome/IL-12 pDNA complexes. The number of metastatic tumor cells (colon26/Luc) was quantitatively evaluated by measuring luciferase activity. ATRA-cationic liposome/IL-12 pDNA complexes reduced the number of colon26/Luc cells and tumor nodules in lungs. ATRA-cationic liposome/IL-12 pDNA complexes significantly prolonged the survival time of mice, whereas cationic liposome/IL-12 pDNA only slightly prolonged it. ATRA-cationic liposome/IL-12 pDNA complexes increased the TNFR1 mRNA upregulation and the number of apoptotic cells in the lung. Moreover, reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were observed in mice treated with ATRA-cationic liposome/IL-12 pDNA complexes. These results suggest that intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes is an effective method for the treatment of lung metastasis in mice.

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Acknowledgements

This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by Health and Labour Sciences Research Grants for Research on Advanced Medical Technology from the Ministry of Health, Labour and Welfare of Japan and by the Radioisotope Research Center of Kyoto University.

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Authors and Affiliations

  1. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    P Charoensit, S Kawakami, Y Higuchi, F Yamashita & M Hashida

  2. Institute for Innovative NanoBio Drug Discovery and Development, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Y Higuchi

  3. Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan

    M Hashida

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  1. P Charoensit
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Correspondence to M Hashida.

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Charoensit, P., Kawakami, S., Higuchi, Y. et al. Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice. Cancer Gene Ther 17, 512–522 (2010). https://doi.org/10.1038/cgt.2010.12

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