Tumour cell radiosensitization using constitutive (CMV) and radiation inducible (WAF1) promoters to drive the iNOS gene: a novel suicide gene therapy

Jenny Worthington, T Robson, M O'Keeffe, DG Hirst

    Research output: Contribution to journalArticle

    52 Citations (Scopus)

    Abstract

    Nitric oxide (NO.) has many characteristics including cytotoxicity, radiosensitization and anti-angiogenesis, which make it an attractive molecule for use in cancer therapy. We have investigated the use of iNOS gene transfer, driven by both a constitutive (CMV) and X-ray inducible (WAF1) promoter, for generating high concentrations of NO. within tumour cells. We have combined this treatment with radiation to exploit the radiosensitizing properties of this molecule. Transfection of murine RIF-1 tumour cells in vitro with the iNOS constructs resulted in increased iNOS protein levels. Under hypoxic conditions cells were radiosensitized by delivery of both constructs so that these treatments effectively eliminated the radioresistance observed under hypoxic conditions. In vivo transfer of the CMV/iNOS construct by direct tumour injection resulted in a delay (4.2 days) in tumour growth compared with untreated controls. This was equivalent to the effect of 20 Gy X-rays alone. Combination of CMV/iNOS gene transfer with 20 Gy X-rays resulted in a dramatic 19.8 day growth delay compared with controls. Tumours treated with the CMV/iNOS showed large areas of necrosis and abundant apoptosis. We believe that iNOS gene transfer has the potential to be a highly effective treatment in combination with radiotherapy.
    LanguageEnglish
    Pages263-269
    JournalGene Therapy
    Volume9
    Issue number4
    DOIs
    Publication statusPublished - Feb 2002

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    Genetic Therapy
    Suicide
    Radiation
    Genes
    Neoplasms
    X-Rays
    Nitric Oxide
    Therapeutics
    Growth
    Transfection
    Drive
    Necrosis
    Radiotherapy
    Apoptosis
    Injections
    Proteins

    Cite this

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    abstract = "Nitric oxide (NO.) has many characteristics including cytotoxicity, radiosensitization and anti-angiogenesis, which make it an attractive molecule for use in cancer therapy. We have investigated the use of iNOS gene transfer, driven by both a constitutive (CMV) and X-ray inducible (WAF1) promoter, for generating high concentrations of NO. within tumour cells. We have combined this treatment with radiation to exploit the radiosensitizing properties of this molecule. Transfection of murine RIF-1 tumour cells in vitro with the iNOS constructs resulted in increased iNOS protein levels. Under hypoxic conditions cells were radiosensitized by delivery of both constructs so that these treatments effectively eliminated the radioresistance observed under hypoxic conditions. In vivo transfer of the CMV/iNOS construct by direct tumour injection resulted in a delay (4.2 days) in tumour growth compared with untreated controls. This was equivalent to the effect of 20 Gy X-rays alone. Combination of CMV/iNOS gene transfer with 20 Gy X-rays resulted in a dramatic 19.8 day growth delay compared with controls. Tumours treated with the CMV/iNOS showed large areas of necrosis and abundant apoptosis. We believe that iNOS gene transfer has the potential to be a highly effective treatment in combination with radiotherapy.",
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    Tumour cell radiosensitization using constitutive (CMV) and radiation inducible (WAF1) promoters to drive the iNOS gene: a novel suicide gene therapy. / Worthington, Jenny; Robson, T; O'Keeffe, M; Hirst, DG.

    In: Gene Therapy, Vol. 9, No. 4, 02.2002, p. 263-269.

    Research output: Contribution to journalArticle

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    AB - Nitric oxide (NO.) has many characteristics including cytotoxicity, radiosensitization and anti-angiogenesis, which make it an attractive molecule for use in cancer therapy. We have investigated the use of iNOS gene transfer, driven by both a constitutive (CMV) and X-ray inducible (WAF1) promoter, for generating high concentrations of NO. within tumour cells. We have combined this treatment with radiation to exploit the radiosensitizing properties of this molecule. Transfection of murine RIF-1 tumour cells in vitro with the iNOS constructs resulted in increased iNOS protein levels. Under hypoxic conditions cells were radiosensitized by delivery of both constructs so that these treatments effectively eliminated the radioresistance observed under hypoxic conditions. In vivo transfer of the CMV/iNOS construct by direct tumour injection resulted in a delay (4.2 days) in tumour growth compared with untreated controls. This was equivalent to the effect of 20 Gy X-rays alone. Combination of CMV/iNOS gene transfer with 20 Gy X-rays resulted in a dramatic 19.8 day growth delay compared with controls. Tumours treated with the CMV/iNOS showed large areas of necrosis and abundant apoptosis. We believe that iNOS gene transfer has the potential to be a highly effective treatment in combination with radiotherapy.

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