Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy

Epperly, Michael W.; Bray, Jeffrey D.; Kraeger, S.; Zwacka, Ralf M.; Engelhardt, John F.; Travis, Elizabeth L.; Greenberger, Joel S.

doi:10.1038/sj.gt.3300580

Cited by 164 publications

(158 citation statements)

References 55 publications

(62 reference statements)

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“…The data confirm and extend our prior publication showing that IT injections of MnSOD-PL complex transfected normal lung tissue. 1 The data establish that this technique did not result in detectable transgene expression in 3LL-LacZ orthotopic lung tumors in the same mice.…”

Section: Resultsmentioning

confidence: 63%

“…1 There was no detectable difference in irradiation sensitivity of 3LL-LacZ cells when cocultivated with either lung cell population 24 h before irradiation. The D 0 for 3LL-LacZ cells cocultivated with lung cells from mice injected with MnSOD-PL complexes was 0.907 ± 0.032 Gy, compared with a D 0 of 0.934 ± 0.029 Gy for lung cells from control mice.…”

Section: Resultsmentioning

confidence: 88%

“…The lung cells from mice injected with MnSOD- Single cell suspensions prepared from the lungs of control mice or mice that has been injected 24 h earlier with MnSOD-PL complex, as published. 1 Lung cells were mixed with 3LL-LacZ cells at a ratio of 10:1. The mixtures were either irradiated immediately (0 h) or incubated for 24 h and then irradiated from 0 to 8 Gy.…”

Section: Resultsmentioning

confidence: 99%

“…1 Mice injected with 3LL-LacZ cells plus MnSOD-PL complex therapy before 18 Gy irradiation showed 50% survival at 37 days. Mice receiving 3LL-LacZ cells alone showed more rapid tumor growth leading to a 50% survival at 15 days.…”

Section: Figure 3 Survival Of Mice Bearing 3ll-lacz Orthotopic Thoracmentioning

confidence: 98%

“…[1][2][3] Lung expression of human MnSOD by IT injection of plasmid/liposomes was associated with a decrease in subsequent irradiation induction of endogenous murine MnSOD and inflammatory cytokines transforming growth factor-beta (TGF-␤1, TGF-␤2) and tumor necrosis factor-alpha (TNF-␣). [1][2][3] As delivery of gene therapy vectors has become a subject of intense investigation for potential use in the therapy of pulmonary diseases, the use of this route of administration for lung-specific transgene expression has raised several questions. Will vector-mediated pulmonary transgene expression affect other organs and, if so, by what mechanism?…”

Section: Introductionmentioning

confidence: 99%

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Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation

et al. 2000

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To determine whether intratracheal (IT) lung protective manganese superoxide-plasmid/liposomes (MnSOD-PL) complex provided 'bystander' protection of thoracic tumors, mice with orthotopic Lewis lung carcinoma-bacterial ␤-galactosidase gene (3LL-LacZ) were studied. There was no significant difference in irradiation survival of 3LL-LacZ cells irradiated, then cocultured with MnSOD-PL-treated compared with control lung cells (D 0 2.022 and 2.153, respectively), or when irradiation was delivered 24 h after coculture (D 0 0.934 and 0.907, respectively). Tumor-bearing control mice showed 50% survival at 18 days and 10% survival at 21 days. Mice receiving liposomes with no insert or LacZ-PL complex plus 18 Gy had 50% survival at 22 days,

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Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Figure 3 Survival Of Mice Bearing 3ll-lacz Orthotopic Thoracmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation

et al. 2000

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Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene

Stickle

Epperly

Klein

et al. 1999

Radiat. Oncol. Investig.

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Esophagitis is a major toxicity of radiation therapy for nonsmall‐cell lung cancer. Intraesophageal injection of manganese superoxide dismutase (MnSOD) plasmid/liposome complexes (1 mg of the pRK5‐MnSOD plasmid containing the human MnSOD transgene in a 0.15 ml volume of lipofectin) before irradiation was carried out to attempt to prevent irradiation esophagitis. In control noninjected male C3H/HeNsd mice, esophagitis was induced by single fraction 3,500 cGy irradiation. Histopathology at 4 days revealed vacuole formation in squamous lining cells, separation of the squamous layer from the underlying muscle layer, ulceration at 7 days, and dehydration and death by 30 days. MnSOD plasmid/liposome complex‐injected mice showed transcription of the human MnSOD transgene message in esophageal squamous lining cells by nested reverse transcriptase‐polymerase chain reaction (RT‐PCR) increased MnSOD biochemical activity 24 h after injection, decreased vacuole formation at day 4 (P < 0.001) after 3,500 cGy thoracic irradiation, and improved survival (P = 0.0009). In contrast, groups of mice receiving LacZ (bacterial β‐galactosidase gene) plasmid/liposome complexes or liposomes containing no DNA before 3,500 cGy irradiation showed an unaltered irradiation histopathology and decreased survival. Mice receiving intraesophageal MnSOD plasmid/liposomes followed 8 h later by human equivalent doses of Taxol (1.4 mg/kg) and carboplatin (2.5 mg/kg), then 15 h later 3,300 cGy irradiation, showed increased survival, compared with irradiated control or LacZ plasmid/liposome groups. Thus, overexpression of the human MnSOD transgene in the esophagus can prevent irradiation‐induced esophagitis in the mouse model. Radiat. Oncol. Invest. 7:204–217, 1999. © 1999 Wiley‐Liss, Inc.

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Overexpression of the human manganese superoxide dismutase (MnSOD) transgene in subclones of murine hematopoietic progenitor cell line 32D cl 3 decreases irradiation-induced apoptosis but does not alter G2/M or G1/S phase cell cycle arrest

Epperly

Bray

Esocobar

et al. 1999

Radiat. Oncol. Invest.

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To determine whether overexpression of the human MnSOD transgene protected 32D cl 3 hematopoietic progenitor cells from ionizing irradiation, 32D cl 3 cells were co‐electroporated with the pRK5 plasmid containing the human MnSOD transgene and SV2‐neo plasmid with G418‐resistant colonies selected. Two clones (1F2 and 2C6) were identified to overexpress the human MnSOD transgene by nested reverse transcriptase‐polymerase chain reaction (RT‐PCR) and increased biochemical activity. Measurement of irradiation‐induced damage was determined in cells removed from G418 for 1 week before irradiation. Irradiation survival curves, apoptosis tunnel assay, and Comet assay was performed. Cell cycle distribution was determined for each line at 0, 1, 3, 6, 24, and 48 hr after 500 cGy by fixing the cells in 70% ethanol, staining with propidium iodide, and analysis by flow cytometer. Biochemical MnSOD activity in U/mg protein was 2.6 for 32D cl 3 and significantly elevated to 8.4 and 6.6 (P < 0.001) U/mg protein for subclones 1F2 and 2C6, respectively. Irradiation survival curves demonstrated an increased shoulder on the irradiation survival curve for 1F2 and 2C6 cells with an n of 4.95 ± 0.48 (P = 0.042) and 4.95 ± 0.13 (P = 0.011), compared with 2.77 ± 0.20 for 32D cl 3. A higher percent of 32D cl 3 cells demonstrated apoptosis at 24 and 48 hr after 1,000 cGy irradiation, compared with 1F2 and 2C6 cells (at 24 hr, 29.37% ± 2.01% of 32D cl 3 cells were apoptotic compared with 5.21 ± 2.61 (P = 0.018) and 5.27 ± 2.58 (P = 0.004) for 1F2 and 2C6, respectively). Significantly more DNA strand breaks were detected by Comet assay in 32D cl 3 cells (Comet length at 600 cGy of 103.4 ± 50.3 units, compared with 69.7 ± 36.3 (P < 0.001) and 48.9 ± 27.5 (P < 0.001) for 1F2 and 2C6, respectively). In contrast, irradiation‐induced cell cycle arrest was similar between the cell lines with a G2/M phase arrest at 6 hr and a G1/S phase arrest at 24 and 48 hr after irradiation. While overexpression of MnSOD increases the shoulder on the irradiation survival curve of 32D cl 3 cells, decreases irradiation‐induced apoptosis, and DNA strand breaks by Comet assay, irradiation‐induced alterations in cell cycle distribution were not significantly altered. These 32D cl 3 subclonal lines overexpressing MnSOD provide a potentially valuable system with which to study the mechanism of irradiation‐induced cell cycle arrest separate from irradiation‐induced apoptosis. Radiat. Oncol. Invest. 7:331–342, 1999. © 1999 Wiley‐Liss, Inc.

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Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy

Cited by 164 publications

References 55 publications

Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation

Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation

Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene

Overexpression of the human manganese superoxide dismutase (MnSOD) transgene in subclones of murine hematopoietic progenitor cell line 32D cl 3 decreases irradiation-induced apoptosis but does not alter G2/M or G1/S phase cell cycle arrest

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