Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment

Jenny Worthington, HO McCarthy, E Barrett, C Adams, T Robson, DG Hirst

    Research output: Contribution to journalArticle

    53 Citations (Scopus)

    Abstract

    Background Inducible nitric oxide synthase (iNOS) gene therapy has been identified as a potential anti-tumour strategy. A major problem common to most gene therapy strategies is targeting of treatment to the turnout volume. in this study we report on the use of the X-ray-inducible WAF1 promoter to achieve targeting of iNOS expression to the turnout volume. Methods A WAF1/iNOS/liposome complex was injected directly into RIF-1 and HT29 tumours in mice. A 4 Gy dose of X-rays was applied to induce the WAF1 promoter followed, 8 h later, by treatment doses of 10 or 20 Gy. Tumour volume was measured, and growth curves plotted. Results Intra-tumoural injection of WAF1/iNOS combined with a priming dose of X-rays to induce the WAF1 promoter, followed by a treatment dose, resulted in sensitiser enhancement ratios of 2.0 and 1.3 in RIF-1 and HT29 tumours, respectively, compared with radiation treatment alone. PCR analysis of organ tissue after intra-tumoural injection of WAF1/iNOS showed that vector sequences were detected in all tissue tested; however, Western blot analysis revealed that iNOS protein levels were significantly increased only in tumour and the surrounding dermal tissue that had been exposed to the 4 Gy inducing dose. Conclusions iNOS gene therapy in combination with an inducible promoter results in significant tumour cell radiosensitisation. The WAF1 promoter may be a good candidate for a gene therapy as it is silent in normal tissue yet can be induced by the tumour environment. Copyright (C) 2004 John Wiley Sons, Ltd.
    LanguageEnglish
    Pages673-680
    JournalJournal of Gene Medicine
    Volume6
    Issue number6
    DOIs
    Publication statusPublished - Jun 2004

    Fingerprint

    Nitric Oxide Synthase Type II
    Genetic Therapy
    Radiation
    Neoplasms
    X-Rays
    Therapeutics
    Injections
    Tumor Burden
    Liposomes
    Western Blotting
    Polymerase Chain Reaction
    Skin
    Growth
    Proteins

    Cite this

    Worthington, J., McCarthy, HO., Barrett, E., Adams, C., Robson, T., & Hirst, DG. (2004). Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment. Journal of Gene Medicine, 6(6), 673-680. https://doi.org/10.1002/jgm.567
    Worthington, Jenny ; McCarthy, HO ; Barrett, E ; Adams, C ; Robson, T ; Hirst, DG. / Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment. In: Journal of Gene Medicine. 2004 ; Vol. 6, No. 6. pp. 673-680.
    @article{545d64ac4c3d422c8dc0ea65fb9703da,
    title = "Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment",
    abstract = "Background Inducible nitric oxide synthase (iNOS) gene therapy has been identified as a potential anti-tumour strategy. A major problem common to most gene therapy strategies is targeting of treatment to the turnout volume. in this study we report on the use of the X-ray-inducible WAF1 promoter to achieve targeting of iNOS expression to the turnout volume. Methods A WAF1/iNOS/liposome complex was injected directly into RIF-1 and HT29 tumours in mice. A 4 Gy dose of X-rays was applied to induce the WAF1 promoter followed, 8 h later, by treatment doses of 10 or 20 Gy. Tumour volume was measured, and growth curves plotted. Results Intra-tumoural injection of WAF1/iNOS combined with a priming dose of X-rays to induce the WAF1 promoter, followed by a treatment dose, resulted in sensitiser enhancement ratios of 2.0 and 1.3 in RIF-1 and HT29 tumours, respectively, compared with radiation treatment alone. PCR analysis of organ tissue after intra-tumoural injection of WAF1/iNOS showed that vector sequences were detected in all tissue tested; however, Western blot analysis revealed that iNOS protein levels were significantly increased only in tumour and the surrounding dermal tissue that had been exposed to the 4 Gy inducing dose. Conclusions iNOS gene therapy in combination with an inducible promoter results in significant tumour cell radiosensitisation. The WAF1 promoter may be a good candidate for a gene therapy as it is silent in normal tissue yet can be induced by the tumour environment. Copyright (C) 2004 John Wiley Sons, Ltd.",
    author = "Jenny Worthington and HO McCarthy and E Barrett and C Adams and T Robson and DG Hirst",
    year = "2004",
    month = "6",
    doi = "10.1002/jgm.567",
    language = "English",
    volume = "6",
    pages = "673--680",
    journal = "Journal of Gene Medicine",
    issn = "1099-498X",
    number = "6",

    }

    Worthington, J, McCarthy, HO, Barrett, E, Adams, C, Robson, T & Hirst, DG 2004, 'Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment', Journal of Gene Medicine, vol. 6, no. 6, pp. 673-680. https://doi.org/10.1002/jgm.567

    Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment. / Worthington, Jenny; McCarthy, HO; Barrett, E; Adams, C; Robson, T; Hirst, DG.

    In: Journal of Gene Medicine, Vol. 6, No. 6, 06.2004, p. 673-680.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment

    AU - Worthington, Jenny

    AU - McCarthy, HO

    AU - Barrett, E

    AU - Adams, C

    AU - Robson, T

    AU - Hirst, DG

    PY - 2004/6

    Y1 - 2004/6

    N2 - Background Inducible nitric oxide synthase (iNOS) gene therapy has been identified as a potential anti-tumour strategy. A major problem common to most gene therapy strategies is targeting of treatment to the turnout volume. in this study we report on the use of the X-ray-inducible WAF1 promoter to achieve targeting of iNOS expression to the turnout volume. Methods A WAF1/iNOS/liposome complex was injected directly into RIF-1 and HT29 tumours in mice. A 4 Gy dose of X-rays was applied to induce the WAF1 promoter followed, 8 h later, by treatment doses of 10 or 20 Gy. Tumour volume was measured, and growth curves plotted. Results Intra-tumoural injection of WAF1/iNOS combined with a priming dose of X-rays to induce the WAF1 promoter, followed by a treatment dose, resulted in sensitiser enhancement ratios of 2.0 and 1.3 in RIF-1 and HT29 tumours, respectively, compared with radiation treatment alone. PCR analysis of organ tissue after intra-tumoural injection of WAF1/iNOS showed that vector sequences were detected in all tissue tested; however, Western blot analysis revealed that iNOS protein levels were significantly increased only in tumour and the surrounding dermal tissue that had been exposed to the 4 Gy inducing dose. Conclusions iNOS gene therapy in combination with an inducible promoter results in significant tumour cell radiosensitisation. The WAF1 promoter may be a good candidate for a gene therapy as it is silent in normal tissue yet can be induced by the tumour environment. Copyright (C) 2004 John Wiley Sons, Ltd.

    AB - Background Inducible nitric oxide synthase (iNOS) gene therapy has been identified as a potential anti-tumour strategy. A major problem common to most gene therapy strategies is targeting of treatment to the turnout volume. in this study we report on the use of the X-ray-inducible WAF1 promoter to achieve targeting of iNOS expression to the turnout volume. Methods A WAF1/iNOS/liposome complex was injected directly into RIF-1 and HT29 tumours in mice. A 4 Gy dose of X-rays was applied to induce the WAF1 promoter followed, 8 h later, by treatment doses of 10 or 20 Gy. Tumour volume was measured, and growth curves plotted. Results Intra-tumoural injection of WAF1/iNOS combined with a priming dose of X-rays to induce the WAF1 promoter, followed by a treatment dose, resulted in sensitiser enhancement ratios of 2.0 and 1.3 in RIF-1 and HT29 tumours, respectively, compared with radiation treatment alone. PCR analysis of organ tissue after intra-tumoural injection of WAF1/iNOS showed that vector sequences were detected in all tissue tested; however, Western blot analysis revealed that iNOS protein levels were significantly increased only in tumour and the surrounding dermal tissue that had been exposed to the 4 Gy inducing dose. Conclusions iNOS gene therapy in combination with an inducible promoter results in significant tumour cell radiosensitisation. The WAF1 promoter may be a good candidate for a gene therapy as it is silent in normal tissue yet can be induced by the tumour environment. Copyright (C) 2004 John Wiley Sons, Ltd.

    U2 - 10.1002/jgm.567

    DO - 10.1002/jgm.567

    M3 - Article

    VL - 6

    SP - 673

    EP - 680

    JO - Journal of Gene Medicine

    T2 - Journal of Gene Medicine

    JF - Journal of Gene Medicine

    SN - 1099-498X

    IS - 6

    ER -