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• W3023714229 abstract "Purpose/Objective(s)Protection of normal tissue against radiation-induced damage may potentially increase the therapeutic ratio of radiotherapy. A promising strategy for this approach is gene therapy-mediated overexpression of the copper-zinc (CuZnSOD) and manganese superoxide-dismutase (MnSOD). Recombinant adeno-associated virus 2 (rAAV2)-based vectors would be an attractive tool for transferring these genes of interest into the target cell owing to their ability to infect non-dividing cells and their very low risk of insertional mutagenesis. The purpose of this study was to test the modulating effects of the SOD genes on human primary lung fibroblasts (HPLF) during and after irradiation.Materials/MethodsLow passage HPLF (MRC5) cells were transduced with an rAAV2-based vector containing either the TK/eGFP (transduction control; tc), CuZnSOD or MnSOD gene. Cells were harvested on day 3, irradiated (1–6 Gy) and seeded into the respective assays. Gene transfer efficiency and apoptosis were determined using FACS analysis; protein expression and activity by western blot and SOD-activity assay, respectively. The clonogenic survival after irradiation was determined using a colony forming assay.ResultsHPLP cells were readily susceptible to the rAAV2 vectors, as high transduction rates were obtained. Over 80% of the cells expressed the respective SOD three days after transduction at a multiplicity of infection of 100 iu/cell. Overexpression of each SOD was confirmed by western blot. CuZnSOD did not exhibit any radioprotective effects compared to the transduction control, whereas for MnSOD-transduced HPLF a SF ratio of 1.29 ± 0.08-fold (MnSOD/ tc; mean ± SEM) was observed (1–6 Gy, p=0.006; n=4).ConclusionsAfter successful transduction of HPLF cells with an AAV-SOD vector, we were able to show an overexpression of CuZn- and MnSOD. Gene transfer of the MnSOD gene and subsequent irradiation resulted in an increase in clonogenic survival (1.29 ± 0.08-fold) of HPLF cells compared to the respective control. Earlier, we have shown lack of protection in tumour cells (HeLa), thus supporting that MnSOD may increase the therapeutic ratio. rAAV2 vectors are promising tools for the delivery of radioprotective genes in normal tissue such as the lung for pulmonary or intestine cells for prostate irradiation. Purpose/Objective(s)Protection of normal tissue against radiation-induced damage may potentially increase the therapeutic ratio of radiotherapy. A promising strategy for this approach is gene therapy-mediated overexpression of the copper-zinc (CuZnSOD) and manganese superoxide-dismutase (MnSOD). Recombinant adeno-associated virus 2 (rAAV2)-based vectors would be an attractive tool for transferring these genes of interest into the target cell owing to their ability to infect non-dividing cells and their very low risk of insertional mutagenesis. The purpose of this study was to test the modulating effects of the SOD genes on human primary lung fibroblasts (HPLF) during and after irradiation. Protection of normal tissue against radiation-induced damage may potentially increase the therapeutic ratio of radiotherapy. A promising strategy for this approach is gene therapy-mediated overexpression of the copper-zinc (CuZnSOD) and manganese superoxide-dismutase (MnSOD). Recombinant adeno-associated virus 2 (rAAV2)-based vectors would be an attractive tool for transferring these genes of interest into the target cell owing to their ability to infect non-dividing cells and their very low risk of insertional mutagenesis. The purpose of this study was to test the modulating effects of the SOD genes on human primary lung fibroblasts (HPLF) during and after irradiation. Materials/MethodsLow passage HPLF (MRC5) cells were transduced with an rAAV2-based vector containing either the TK/eGFP (transduction control; tc), CuZnSOD or MnSOD gene. Cells were harvested on day 3, irradiated (1–6 Gy) and seeded into the respective assays. Gene transfer efficiency and apoptosis were determined using FACS analysis; protein expression and activity by western blot and SOD-activity assay, respectively. The clonogenic survival after irradiation was determined using a colony forming assay. Low passage HPLF (MRC5) cells were transduced with an rAAV2-based vector containing either the TK/eGFP (transduction control; tc), CuZnSOD or MnSOD gene. Cells were harvested on day 3, irradiated (1–6 Gy) and seeded into the respective assays. Gene transfer efficiency and apoptosis were determined using FACS analysis; protein expression and activity by western blot and SOD-activity assay, respectively. The clonogenic survival after irradiation was determined using a colony forming assay. ResultsHPLP cells were readily susceptible to the rAAV2 vectors, as high transduction rates were obtained. Over 80% of the cells expressed the respective SOD three days after transduction at a multiplicity of infection of 100 iu/cell. Overexpression of each SOD was confirmed by western blot. CuZnSOD did not exhibit any radioprotective effects compared to the transduction control, whereas for MnSOD-transduced HPLF a SF ratio of 1.29 ± 0.08-fold (MnSOD/ tc; mean ± SEM) was observed (1–6 Gy, p=0.006; n=4). HPLP cells were readily susceptible to the rAAV2 vectors, as high transduction rates were obtained. Over 80% of the cells expressed the respective SOD three days after transduction at a multiplicity of infection of 100 iu/cell. Overexpression of each SOD was confirmed by western blot. CuZnSOD did not exhibit any radioprotective effects compared to the transduction control, whereas for MnSOD-transduced HPLF a SF ratio of 1.29 ± 0.08-fold (MnSOD/ tc; mean ± SEM) was observed (1–6 Gy, p=0.006; n=4). ConclusionsAfter successful transduction of HPLF cells with an AAV-SOD vector, we were able to show an overexpression of CuZn- and MnSOD. Gene transfer of the MnSOD gene and subsequent irradiation resulted in an increase in clonogenic survival (1.29 ± 0.08-fold) of HPLF cells compared to the respective control. Earlier, we have shown lack of protection in tumour cells (HeLa), thus supporting that MnSOD may increase the therapeutic ratio. rAAV2 vectors are promising tools for the delivery of radioprotective genes in normal tissue such as the lung for pulmonary or intestine cells for prostate irradiation. After successful transduction of HPLF cells with an AAV-SOD vector, we were able to show an overexpression of CuZn- and MnSOD. Gene transfer of the MnSOD gene and subsequent irradiation resulted in an increase in clonogenic survival (1.29 ± 0.08-fold) of HPLF cells compared to the respective control. Earlier, we have shown lack of protection in tumour cells (HeLa), thus supporting that MnSOD may increase the therapeutic ratio. rAAV2 vectors are promising tools for the delivery of radioprotective genes in normal tissue such as the lung for pulmonary or intestine cells for prostate irradiation." @default.
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• W3023714229 date "2006-11-01" @default.
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