Manganese superoxide dismutase gene therapy protects against irradiation-induced cystitis

Kanai, Anthony; Zeidel, Mark L.; Lavelle, John P.; Greenberger, Joel S.; Birder, Lori A.; Groat, William C. de; Apodaca, Gerard; Meyers, Susan; Ramage, Richard; Epperly, Michael W.

doi:10.1152/ajprenal.00228.2002

Cited by 59 publications

(56 citation statements)

References 42 publications

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“…Irradiated urinary bladders in animal models undergo pathological changes in three phases. 25 The first phase is the acute damage consisting of urothelial swelling, ulceration, and vascular endothelial cell damage. 26,27 The second phase is the infiltration of inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Imamura

Ishizuka

Zhang

et al. 2012

Tissue Engineering Part A

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The purpose of this study was to determine whether bone marrow-derived cells implanted into radiation-injured urinary bladders could reconstruct functional bladder tissues. The pelvic region of anesthetized female SpragueDawley (SD) rats was irradiated with 2 Gy once a week for 5 weeks. After the last irradiation, the rats were maintained for 2 weeks. Bone marrow cells were harvested from the femurs of donor male green fluorescence protein (GFP)-transfected SD rats and cultured for 7 days. Two weeks after the last radiation exposure, the cultured adherent, proliferating bone marrow-derived cells were implanted into the walls of irradiated urinary bladders. For controls, cell-free solutions were similarly injected. Four weeks after donor cell or control implantations, cystometric, histological, and immunohistochemical investigations were performed. Two weeks after the last irradiation, the smooth muscle layers and nerve fibers of the irradiated urinary bladders were disorganized. The proportions of smooth muscle layer and nerve fiber areas were significantly decreased compared with sham-irradiated urinary bladders. In addition, the remaining smooth muscle cells within the irradiated urinary bladders expressed P4HB, an indicator of collagen synthesis. In the cystometric investigations, the voiding interval of irradiated rats was irregularly prolonged, 7.92 -1.09 min, and the residual volume, 0.13 -0.03 mL, was significantly higher compared with the sham-irradiated rats (5.50 -0.43 mL and 0.05 -0.01 mL). After 4 weeks, the smooth muscle layers and nerve fibers in the cell-free control urinary bladders remained similar to the preimplanted irradiated urinary bladders; however, the cell-implanted urinary bladders contained reconstructed smooth muscle layers and nerve fibers, the proportions of each were significantly higher than those in the cell-free injected controls. The expression of P4HB within the cell-implanted urinary bladders decreased. Some GFPpositive implanted cells differentiated into smooth muscle-and nerve-like cells and became organized into the reconstructed tissues. The voiding interval of the cell-implanted rats, 5.46 -0.33 min, was regular and similar to that of the sham-irradiated rats, and significantly less than that of the cell-free injected controls, 7.39 -0.54 min. The residual volume, 0.04 -0.01 mL, was similar to that of the sham-irradiated rats and significantly decreased compared with that of the cell-free injected controls, 0.15 -0.05 mL. Therefore, the implantation of bone marrowderived cells is a potentially useful treatment for radiotherapy-induced urinary dysfunctions.

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Section: Discussionmentioning

confidence: 99%

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Imamura

Ishizuka

Zhang

et al. 2012

Tissue Engineering Part A

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“…51 However, by using a construct of the Cu/ZnSOD transgene to which was attached the mitochondrial localization signal of MnSOD, an effective transgene protein for radioprotection was demonstrated. 51 MnSOD-PL administration prior to irradiation of lung, 12 oral cavity, 21 esophagus, 17 bladder, 22 and intestine 23 has Lung irradiation protection by inhalation of MnSOD-PL M Carpenter et al been shown to provide radioprotection in each organ's target volume. In two model systems (lung and oral cavity), orthotopic tumors were not detectably protected from irradiation killing under conditions of normal tissue radiation protection.…”

Section: Lung Irradiation Protection By Inhalation Of Mnsod-pl M Carpmentioning

confidence: 99%

“…2,3,5,6 A biological response modifier approach toward decreasing pulmonary toxicity would be valuable to facilitate new improvements in radiation treatment. We have demonstrated that organ-specific (lung, [12][13][14][15][16] esophagus, [17][18][19][20] oral cavity, 21 bladder, 22 or intestine 23 ) introduction of the human manganese superoxide dismutase (MnSOD) transgene by plasmid/liposomes (MnSOD-PL) or viral vectors is associated with significant uptake, increased transgene mRNA and protein availability for 48-72 h after administration, and significant protection from ionizing radiation-induced acute and chronic organ injury. 24 In both pulmonary and esophageal radiation protection models, intratracheal or intraoral administration of MnSOD-PL was shown to delay the onset of organizing alveolitis/fibrosis and esophagitis in C57BL/ 6J mice, respectively, and improve overall survival in single-or multifraction radiotherapy protocols.…”

Section: Introductionmentioning

confidence: 99%

Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

et al. 2005

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Intratracheal injection of manganese superoxide dismutaseplasmid/liposome (MnSOD-PL) complexes has been demonstrated to delay the onset and reduce the extent of ionizing irradiation-induced murine pulmonary organizing alveolitis/ fibrosis. To facilitate translation of this modality to clinical fractionated radiotherapy, inhalation delivery of MnSOD-PL was developed using an ultrasonic nebulizer. Transgene product was quantitated by immunohistochemical quantitation and pulmonary tissue levels of MnSOD biochemical activity. C57BL/6NHsd female mice demonstrated a plasmid dose-dependent increased expression of MnSOD transgene product over the range of 250 mg-2.5 mg of MnSOD-PL administered over a constant 5 min interval. Delivery of a constant concentration of 500 mg of MnSOD-PL with varying times of administration ranging from 0.5 to 10 min demonstrated optimal MnSOD expression at 5 min. Mice pretreated by inhalation delivery of MnSOD-PL demonstrated significantly improved survival after 20 Gy single fraction irradiation to both lungs compared to LacZ-PL inhalation-treated or irradiated control mice. Mice receiving 10 fractions of 3.5 cGy demonstrated increased pulmonary MnSOD transgene product activity by a protocol of every Monday-Wednesday or daily inhalation of MnSOD-PL. Thus, inhalation radioprotective gene therapy using MnSOD-PL provides a practical and effective method for delivery of lung-specific radioprotection during fractionated radiotherapy protocols in a mouse model. Gene Therapy (2005) 12, 685-693.

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“…If future studies confirm that SOD2 expression are associated with a tumor residual or confer a radioresistance when a particular radiation treatment-planning method is used, then identifying patients with tumors that carry increased SOD2 may improve treatment selection. Furthermore, regulating the expression of SOD2 in vitro and in mouse model has improved the sensitization of cell lines and experimental tumors to radiation therapy, or the protection of the haematopoietic compartment and normal tissues from the effects of ionizing radiation, demonstrating the effectiveness of a combination of gene therapy and conventional radiotherapy (10,15,(44)(45)(46). Accurate detection of SOD2 status prior to therapy will also allow SOD2 inhibitors or radiosensitizers to be used in clinical trials in NPC to reduce failure from radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Identifying SOD2 gene could therefore yield crucial insights into the genes in radioresistant phenotypes. ONCOLOGY REPORTS 23: 1005-1011, 2010 The effect on radioresistance of manganese superoxide dismutase in nasopharyngeal carcinoma…”

Section: Introductionmentioning

confidence: 99%

The effect on radioresistance of manganese superoxide dismutase in nasopharyngeal carcinoma

Zhang²,

Zhao³

et al. 2010

Oncol Rep

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Abstract. Failure to control nasopharyngeal carcinomas (NPC) is mainly due to a portion of radioresistant phenotype. Identifying gene targets for radiosensitization is an important strategy in improving anticancer treatments. Exposure of cells to ionizing radiation leads to the formation of reactive oxygen species that are associated with radiation-induced cellular apoptosis and necrosis. The antioxidant enzyme manganese superoxide dismutase (SOD2) catalyzes the dismutation of the superoxide anions into hydrogen peroxide. We reasoned that SOD2 could contribute to the radioresistant phenotype in NPC cells. We compared CNE1 cells with CNE2 cells in radiation character and SOD2 protein. SOD2 gene silencing through the plasmid transfer using a microRNA interference optimized for transcription in NPC cell lines inhibited the radioresistance of human NPC cells. We compared radioresistant NPC with radiosensitive NPC in SOD2 expression. CNE1 cells and CNE2 cells demonstrated dose-modifying factors at 10% isosurvival of 1.529 and 1. CNE1 cells were 1.94-fold higher than CNE2 cells at SOD2 protein baseline, and CNE1 cells exposed to ionizing radiation demonstrated 1.15-to 1.39-fold increase in SOD2 immunoreactive protein. Radioresistance in CNE1 cells was reduced following expression of miRNA targeting SOD2. Radioresistant tumors (11/23) were SOD2-positive, and 2/46 radiosensitive tumors were SOD2-positive before commencement of radiotherapy. The results presented suggest that SOD2 expression can participate in radioresistance of NPC, being markers of a subset of tumors in which routine radiation treatment failure is likely. Combination of the SOD2 gene silencing therapy and conventional radiotherapy should be attempted to improved cancer therapy for NPC.

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Manganese superoxide dismutase gene therapy protects against irradiation-induced cystitis

Cited by 59 publications

References 42 publications

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Bone Marrow-Derived Cells Implanted into Radiation-Injured Urinary Bladders Reconstruct Functional Bladder Tissues in Rats

Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage

The effect on radioresistance of manganese superoxide dismutase in nasopharyngeal carcinoma

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