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 tumour volume. In this study we report on the use of the X-ray-inducible WAF1 promoter to achieve targeting of iNOS expression to the tumour 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 2004 John Wiley & Sons, Ltd.
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 tumour volume. In this study we report on the use of the X-ray-inducible WAF1 promoter to achieve targeting of iNOS expression to the tumour 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 2004 John Wiley & Sons, Ltd.
Authors: V Kostourou; J E Cartwright; A P Johnstone; J K R Boult; E R Cullis; Gstj Whitley; S P Robinson Journal: Br J Cancer Date: 2010-12-07 Impact factor: 7.640
Authors: Cian M McCrudden; John W McBride; Joanne McCaffrey; Ahlam A Ali; Nicholas J Dunne; Vicky L Kett; Jonathan A Coulter; Tracy Robson; Helen O McCarthy Journal: Mol Ther Nucleic Acids Date: 2016-12-31 Impact factor: 8.886