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Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

Gene Therapy volume 16, pages 1395–1404 (2009)Cite this article

Abstract

Cancer gene therapy by adenovirus vectors (Advs) for metastatic cancer is limited because systemic administration of Adv produces low therapeutic effect and severe side effects. In this study, we generated a dual cancer-specific targeting vector system by using PEGylation and the telomere reverse transcriptase (TERT) promoter and attempted to treat experimental metastases through systemic administration of the vectors. We first optimized the molecular size of PEG and modification ratios used to create PEG-Ads. Systemic administration of PEG-Ad with 20-kDa PEG at a 45% modification ratio (PEG[20K/45%]-Ad) resulted in higher tumor-selective transgene expression than unmodified Adv. Next, we examined the effectiveness against metastases and side effects of a TERT promoter-driven PEG[20K/45%]-Ad containing the herpes simplex virus thymidine kinase (HSVtk) gene (PEG-Ad-TERT/HSVtk). Systemic administration of PEG-Ad-TERT/HSVtk showed superior antitumor effects against metastases with negligible side effects. A cytomegalovirus (CMV) promoter-driven PEG[20K/45%]-Ad also produced antimetastatic effects, but these were accompanied by side effects. Combining PEG-Ad-TERT/HSVtk with etoposide or 5-fluorouracil enhanced the therapeutic effects with negligible side effects. These results suggest that modification with 20-kDa PEG at a 45% modification ratio is the optimal condition for PEGylation of Adv, and PEG-Ad-TERT/HSVtk is a prototype Adv for systemic cancer gene therapy against metastases.

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Acknowledgements

This study was supported in part by grants from the Ministry of Health, Labor, and Welfare in Japan and by the Research on Health Sciences focusing on Drug Innovation from the Japan Health Sciences Foundation.

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Author notes

  1. X Yao, Y Yoshioka and T Morishige: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

    X Yao, Y Yoshioka, T Morishige, Y Eto, H Watanabe, Y Mukai, N Okada & S Nakagawa

  2. The Center for Advanced Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan

    Y Yoshioka & S Nakagawa

  3. Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    Y Okada

  4. Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

    H Mizuguchi

  5. Department of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

    H Mizuguchi

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  1. X Yao
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Correspondence to Y Yoshioka or S Nakagawa.

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Yao, X., Yoshioka, Y., Morishige, T. et al. Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis. Gene Ther 16, 1395–1404 (2009). https://doi.org/10.1038/gt.2009.95

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