Hong Wang

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (47)97.06 Total impact

  • Practical Radiation Oncology. 11/2014;
  • Experimental hematology. 08/2014; 42(8S):S32.
  • Experimental hematology. 08/2014; 42(8S):S32.
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    ABSTRACT: The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2(-/-) mice, comparing this to Fancd2(+/-) and Fancd2(+/+) mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10-12-week-old mice, of FVB/N background Fancd2(-/-), Fancd2(+/-) and Fancd2(+/+) were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2(-/-) mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2(+/+) mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2(-/-) mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2(+/+) mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2(-/-) mice compared to Fancd2(+/+) controls. Fancd2(-/-) mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head- and neck-irradiated Fancd2(+/+) mice. In radiosensitive Fancd2(-/-) mice, biomarkers of both local oral cavity and distant marrow radiation toxicity were ameliorated by intraoral JP4-039/F15. We propose that Fancd2(-/-) mice are a valuable radiosensitive animal model system, which can be used to evaluate potential radioprotective agents.
    Radiation research. 06/2014;
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    ABSTRACT: FancD2 plays a central role in the human Fanconi anemia DNA damage response (DDR) pathway. Fancd2(-/-) mice exhibit many features of human Fanconi anemia including cellular DNA repair defects. Whether the DNA repair defect in Fancd2(-/-) mice results in radiologic changes in all cell lineages is unknown. We measured stress of hematopoiesis in long-term marrow cultures and radiosensitivity in clonogenic survival curves, as well as comet tail intensity, total antioxidant stores and radiation-induced gene expression in hematopoietic progenitor compared to bone marrow stromal cell lines. We further evaluated radioprotection by a mitochondrial-targeted antioxidant GS-nitroxide, JP4-039. Hematopoiesis longevity in Fancd2(-/-) mouse long-term marrow cultures was diminished and bone marrow stromal cell lines were radiosensitive compared to Fancd2(+/+) stromal cells (Fancd2(-/-) D0 = 1.4 ± 0.1 Gy, ñ = 5.0 ± 0.6 vs. Fancd2(+/+) D0 = 1.6 ± 0.1 Gy, ñ = 6.7 ± 1.6), P = 0.0124 for D0 and P = 0.0023 for ñ, respectively). In contrast, Fancd2(-/-) IL-3-dependent hematopoietic progenitor cells were radioresistant (D0 = 1.71 ± 0.04 Gy and ñ = 5.07 ± 0.52) compared to Fancd2(+/+) (D0 = 1.39 ± 0.09 Gy and ñ = 2.31 ± 0.85, P = 0.001 for D0). CFU-GM from freshly explanted Fancd2(-/-) marrow was also radioresistant. Consistent with radiosensitivity, irradiated Fancd2(-/-) stromal cells had higher DNA damage by comet tail intensity assay compared to Fancd2(+/+) cells (P < 0.0001), slower DNA damage recovery, lower baseline total antioxidant capacity, enhanced radiation-induced depletion of antioxidants, and increased CDKN1A-p21 gene transcripts and protein. Consistent with radioresistance, Fancd2(-/-) IL-3-dependent hematopoietic cells had higher baseline and post irradiation total antioxidant capacity. While, there was no detectable alteration of radiation-induced cell cycle arrest with Fancd2(-/-) stromal cells, hematopoietic progenitor cells showed reduced G2/M cell cycle arrest. The absence of the mouse Fancd2 gene product confers radiosensitivity to bone marrow stromal but not hematopoietic progenitor cells.
    Radiation Research 01/2014; · 2.70 Impact Factor
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    ABSTRACT: A water-soluble ionizing radiation mitigator would have considerable advantages for the management of acute and chronic effects of ionizing radiation. We report that a novel oxetanyl sulfoxide (MMS350) is effective both as a protector and a mitigator of clonal mouse bone marrow stromal cell lines in vitro, and is an effective in vivo mitigator when administered 24 h after 9.5 Gy (LD100/30) total-body irradiation of C57BL/6NHsd mice, significantly improving survival (P = 0.0097). Furthermore, MMS350 (400 μM) added weekly to drinking water after 20 Gy thoracic irradiation significantly decreased: expression of pulmonary inflammatory and profibrotic gene transcripts and proteins; migration into the lungs of bone marrow origin luciferase+/GFP+ (luc+/GFP+) fibroblast progenitors (in both luc+ marrow chimeric and luc+ stromal cell line injected mouse models) and decreased radiation-induced pulmonary fibrosis (P < 0.0001). This nontoxic and orally administered small molecule may be an effective therapeutic in clinical radiotherapy and as a counter measure against the acute and chronic effects of ionizing radiation.
    Radiation Research 10/2013; · 2.70 Impact Factor
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    ABSTRACT: We evaluated the use of colony formation (CFU-GM, BFU-E, and CFU-GEMM) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. Each of 11 compounds was added before (protection) or after (mitigation) ionizing irradiation including: GS-nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor LY294002), TPP-imidazole fatty acid, (TPP-IOA), the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propanolol, and the ATP sensitive potassium channel blocker (glyburide). The drugs XJB-5-131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs, XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU-GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs that were effective in murine assays: TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide showed no significant protection or mitigation in human CB assays. These data support testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, reducing the need for animal experiments.
    Experimental hematology 08/2013; · 3.11 Impact Factor
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    ABSTRACT: Mitochondrial targeted manganese superoxide dismutase is a major antioxidant enzyme, the levels of which modulate the response of cells, tissues and organs to ionizing irradiation. We developed a Tet-regulated MnSOD mouse (MnSOD(tet)) to examine the detailed relationship between cellular MnSOD concentration and radioresistance and carried out in vitro studies using bone marrow culture derived stromal cell lines (mesenchymal stem cells). Homozygous MnSOD(tet/tet) cells had low levels of MnSOD, reduced viability and proliferation, increased radiosensitivity, elevated overall antioxidant stores, and defects in cell proliferation and DNA strand-break repair. Doxycycline (doxy) treatment of MnSOD(tet/tet) cells increased MnSOD levels and radioresistance from ñ of 2.79 ± 1.04 to 8.69 ± 1.09 (P = 0.0060) and normalized other biologic parameters. In contrast, MnSOD(tet/tet) cells showed minimal difference in baseline and radiation induced mRNA and protein levels of TGF-β, Nrf2 and NF-κB and radiation induced cell cycle arrest was not dependent upon MnSOD level. These novel MnSOD(tet/tet) mouse derived cells should be valuable for elucidating several parameters of the oxidative stress response to ionizing radiation.
    Radiation Research 07/2013; · 2.70 Impact Factor
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    ABSTRACT: Carbamazepine, a sodium channel blocker and pro-autophagy agent used in the treatment of epilepsy and trigeminal neuralgia, is also an ionizing radiation mitigator and protector. We measured the effect of carbamazepine, compared to other pro-autophagy drugs (i.e. lithium and valproic acid), on irradiation of autophagy incompetent (Atg5(-/-)) and competent (Atg5(+/+)) mouse embryonic fibroblasts, p53(-/-) and p53(+/+) bone marrow stromal cells, and human IB3, KM101, HeLa, and umbilical cord blood cell and in total body-irradiated or orthotopic tumor-bearing mice. Carbamazepine, but not other pro-autophagy drugs, was a radiation protector and mitigator for mouse cell lines, independent of apoptosis, autophagy, p53, antioxidant store depletion, and class I phosphatidylinositol 3-kinase, but was ineffective with human cells. Carbamazepine was effective when delivered 24 hours before or 12 hours after total body irradiation of C57BL/6HNsd mice and did not protect orthotopic Lewis lung tumors. Carbamazepine is a murine radiation protector and mitigator.
    In vivo (Athens, Greece) 05/2012; 26(3):341-54. · 1.15 Impact Factor
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    ABSTRACT: The senescence accelerated-prone mouse variant 6 (SAMP6) shows normal growth followed by rapid aging, development of osteopenia, and shortened lifespan, compared with control R1 mice. Because oxidative stress is a fundamental mechanism of tissue aging, we tested whether cellular parameters that are associated with oxidative stress are impaired with marrow from SAMP6 mice. We compared in vitro hematopoiesis, irradiation sensitivity, proliferative potential, and osteoblastogenesis with marrow cells from SAMP6 and R1 mice. Marrow cells from SAMP6 mice showed shortened in vitro hematopoiesis; their stromal cells showed greater radiation sensitivity and decreased proliferation. Consistent with those properties, there was constitutive upregulation of transforming growth factor-β(1), an inhibitor of hematopoiesis, and of cell cycle inhibitory genes, p16(INK4A) and p19(ARF). Paradoxically, there was constitutive expression of osteoblast genes in stromal cells from SAMP6 mice, but in vitro matrix mineralization was impaired. These studies and data included in other reports indicate that impaired proliferation of osteoblast progenitors in SAMP6 marrow may be a major factor contributing to accelerated loss of bone mass. In sum, marrow from SAMP6 mice had diminished capacity for long-term hematopoiesis, increased radiosensitivity, and reduced proliferative capacity.
    Experimental hematology 02/2012; 40(6):499-509. · 3.11 Impact Factor
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    ABSTRACT: The effect of lung irradiation on reduction of lung stem cells and repopulation with bone marrow-derived cells was measured. Expression of green fluorescent protein positive cells (GFP(+)) in the lungs of thoracic irradiated FVB/NHsd mice (Harlan Sprague Dawley, Indianapolis, IN, USA) was determined. This was compared to the repopulation of bone marrow-derived cells found in the lungs from naphthalene treated male FVB/NHsd mice and gangciclovir (GCV) treated FeVBN GFP(+) male marrow chimeric HSV-TK-CCSP. The level of mRNA for lung stem cell markers clara cell (CCSP), epithelium 1 (FOXJ1) and surfactant protein C (SP-C), and sorted single cells positive for marrow origin epithelial cells (GFP(+)CD45(-)) was measured. The expression of pulmonary stem cells as determined by PCR was reduced most by GCV, then naphthalene, and least by thoracic irradiation. Irradiation, like GCV, reduced mRNA expression of CCSP, CYP2F2, and FOXJ1, while naphthalene reduced that of CCSP and CYP2F2. Ultrastructural analysis showed GFP(+) pulmonary cells of bone marrow origin, with the highest frequency being found in GCV-treated groups. Bone marrow progenitor cells may not participate in the repopulation of the lung following irradiation.
    In vivo (Athens, Greece) 01/2012; 26(1):9-18. · 1.15 Impact Factor
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    ABSTRACT: Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG(-/-) (PD326) and FancD2(-/-) (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2(-/-) cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG(-/-) cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2(-/-) cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2(-/-) cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients.
    Radiation Research 09/2011; 176(5):603-12. · 2.70 Impact Factor
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    ABSTRACT: To determine whether Carbamazepine (CBZ) is a radiation protector and/or mitigator. Murine hematopoietic progenitor 32D cl 3 cells were incubated in 1, 10, or 100 μM CBZ 1 h before or immediately after 0-8 Gy irradiation and assayed for clonogenic survival. Autophagy was assayed by immunoblot for microtubule-associated protein light chain 3 (LC3). In vivo radioprotection and mitigation were determined with C57BL/6NTac mice. CBZ treatment at 1, 10 or 100 μM for 1 h prior to irradiation increased radioresistance (the dose for 37% survival or D(0)) from control 1.5 ± 0.1 Gy to 2.1 ± 0.2 Gy (P = 0.012), 2.3 ± 0.1 Gy (P = 0.010), and 3.6 ± 0.7 Gy (P = 0.003), respectively; after irradiation increased the extrapolation number (ñ) from 1.5 ± 0.3 to 10.1 ± 4.2 (P = 0.011), 5.5 ± 1.7 (P = 0.019), and 3.6 ± 0.8 (P = 0.014), respectively, and increased autophagy. CBZ treated mice 10 min or 24 h before or 10 min or 12 h after 9.25 Gy total body irradiation (TBI) showed increased survival (P = 0.012, 0.011, 0.0002, and 0.017, respectively). CBZ may be a useful radiation protector and mitigator.
    International Journal of Radiation Biology 07/2011; 87(10):1052-60. · 1.84 Impact Factor
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    ABSTRACT: To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules. We evaluated the ability of nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere MCF201-89, and the p53/mdm2/mdm4 protein complex inhibitor BEB55 to mitigate radiation effects by clonogenic survival curves with the murine hematopoietic progenitor cell line 32D cl 3 and the human bone marrow stromal (KM101) and pulmonary epithelial (IB3) cell lines. The p53-dependent mechanism of action was tested with p53(+/+) and p53(-/-) murine bone marrow stromal cell lines. C57BL/6 NHsd female mice were injected i.p. with JP4-039, MCF201-89, or BEB55 individually or in combination, after receiving 9.5 Gy total body irradiation (TBI). Each drug, JP4-039, MCF201-89, or BEB55, individually or as a mixture of all three compounds increased the survival of 32D cl 3 (p = 0.0021, p = 0.0011, p = 0.0038, and p = 0.0073, respectively) and IB3 cells (p = 0.0193, p = 0.0452, p = 0.0017, and p = 0.0019, respectively) significantly relative to that of control irradiated cells. KM101 cells were protected by individual drugs (p = 0.0007, p = 0.0235, p = 0.0044, respectively). JP4-039 and MCF201-89 increased irradiation survival of both p53(+/+) (p = 0.0396 and p = 0.0071, respectively) and p53(-/-) cells (p = 0.0007 and p = 0.0188, respectively), while BEB55 was ineffective with p53(-/-) cells. Drugs administered individually or as a mixtures of all three after TBI significantly increased mouse survival (p = 0.0234, 0.0009, 0.0052, and 0.0167, respectively). Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice.
    International journal of radiation oncology, biology, physics 07/2011; 80(3):860-8. · 4.59 Impact Factor
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    ABSTRACT: Abstract Many acute and chronic effects of ionizing radiation are mediated by reactive oxygen species and reactive nitrogen species, which deplete antioxidant stores, leading to cellular apoptosis, stem cell depletion and accelerated aging. C57BL/6NHsd mice receiving intravenous MnSOD-PL prior to 9.5 Gy total-body irradiation (TBI) show increased survival from the acute hematopoietic syndrome, and males demonstrated improved long-term survival (Epperly et al., Radiat. Res. 170, 437-444, 2008). We evaluated the effect of an antioxidant-chemopreventive diet compared to a regular diet on long-term survival in female mice. Twenty-four hours before the LD(50/30) dose of 9.5 Gy TBI, subgroups of mice were injected intravenously with MnSOD-PL (100 μg plasmid DNA in 100 μl of liposomes). Mice on either diet treated with MnSOD-PL showed decreased death after irradiation compared to irradiated mice on the house diet alone (P = 0.031 for the house diet plus MnSOD-PL or 0.015 for antioxidant diet plus MnSOD-PL). The mice on the antioxidant-chemoprevention diet alone or with MnSOD-PL that survived 30 days after irradiation had a significant increase in survival compared to mice on the regular diet (P = 0.04 or 0.01, respectively). In addition, mice treated with MnSOD-PL only and surviving 30 days after radiation also had increased survival compared to those on the regular diet alone (P = 0.02). Survivors of acute ionizing radiation damage have ameliorated life shortening if they are fed an antioxidant-chemopreventive diet.
    Radiation Research 04/2011; 175(6):759-65. · 2.70 Impact Factor
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    ABSTRACT: Total-body irradiation (TBI) doses in the range of 2-8 Gy are associated with a drop in peripheral blood counts, decreased bone marrow cellularity, and hematopoietic syndrome. Radiation mitigators must be safe for individuals likely to recover spontaneously. Female C57BL/6HNsd mice exposed to 9.0 and 9.15 Gy TBI, received intraperitoneal (10 mg/kg) JP4-039, a novel radiation mitigator, 24 hours after irradiation and were followed for hematopoietic recovery. Irradiated mice showed reduced peripheral blood lymphocytes and neutrophils and bone marrow cellularity at day 5. Serum electrolytes, liver and renal function tests showed no deleterious effect of JP4-039-after irradiation, and no reduction in survival compared to irradiated controls. Marrow recovery measured as cellularity, and hematopoietic colony-forming cells including primitive granulocyte-erythroid-megakaryocyte-monocytes (GEMM), reached pre-irradiation levels by day 30 in JP4-039 treated groups. Mice receiving single or multiple administrations of JP4-039 showed an early return of CFU-GEMM. JP4-039 (GS-Nitroxide) is a safe radiation mitigator in mice warranting studies in larger animals and potentially a Phase I Clinical Trial.
    In vivo (Athens, Greece) 01/2011; 25(3):315-23. · 1.15 Impact Factor
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    ABSTRACT: The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of haemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids that blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its haem-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1 h before through 24 h after the irradiation.
    Nature Communications 01/2011; 2:497. · 10.74 Impact Factor
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    ABSTRACT: Esophagitis is a significant toxicity of radiation therapy for lung cancer. In this study, reduction of irradiation esophagitis in mice, by orally administered p53/Mdm2/Mdm4 inhibitor, BEB55, or the GS-nitroxide, JP4-039, was evaluated. BEB55 or JP4-039 in F15 (liposomal) formulation was administered intraesophageally to C57BL/6 mice prior to thoracic irradiation of 29 Gy × 1 or 11.5 Gy × 4 thoracic irradiation. Progenitor cells were sorted from excised esophagus, and nitroxide was quantified, by electron paramagnetic resonance (EPR). Mice with Lewis lung carcinoma (3LL) orthotopic lung tumors were treated with BEB55 or JP4-039 prior to 20 Gy to determine if the drugs would protect the tumor cells from radiation. Intraesophageal BEB55 and JP4-039 compared to formulation alone increased survival after single fraction (p=0.0209 and 0.0384, respectively) and four fraction thoracic irradiation (p=0.0241 and 0.0388, respectively). JP4-039 was detected in esophagus, liver, bone marrow, and orthotopic Lewis lung carcinoma (3LL) tumor. There was no significant radiation protection of lung tumors by BEB55 or JP4-039 compared to formulation only as assessed by survival (p=0.3021 and 0.3693, respectively). Thus, BEB55 and JP4-039 safely ameliorate radiation esophagitis in mice.
    In vivo (Athens, Greece) 01/2011; 25(6):841-8. · 1.15 Impact Factor
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    ABSTRACT: The effect of deletion of the nitric oxide synthase 1 gene (NOS1(-/-)) on radiosensitivity was determined. In vitro, long-term cultures of bone marrow stromal cells derived from NOS1(-/-) were more radioresistant than cells from C57BL/6NHsd (wild-type), NOS2(-/-) or NOS3(-/-) mice. Mice from each strain received 20 Gy thoracic irradiation or 9.5 Gy total-body irradiation (TBI), and NOS1(-/-) mice were more sensitive to both. To determine the etiology of radiosensitivity, studies of histopathology, lower esophageal contractility, gastrointestinal transit, blood counts, electrolytes and inflammatory markers were performed; no significant differences between irradiated NOS1(-/-) and control mice were found. Video camera surveillance revealed the cause of death in NOS1(-/-) mice to be grand mal seizures; control mice died with fatigue and listlessness associated with low blood counts after TBI. NOS1(-/-) mice were not sensitive to brain-only irradiation. MnSOD-PL therapy delivered to the esophagus of wild-type and NOS1(-/-) mice resulted in equivalent biochemical levels in both; however, in NOS1(-/-) mice, MnSOD-PL significantly increased survival after both thoracic and total-body irradiation. The mechanism of radiosensitivity of NOS1(-/-) mice and its reversal by MnSOD-PL may be related to the developmental esophageal enteric neuronal innervation abnormalities described in these mice.
    Radiation Research 09/2010; 174(3):297-312. · 2.70 Impact Factor
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    ABSTRACT: Radiation-induced DNA damage is a precursor to mutagenesis and cytotoxicity. During radiotherapy, exposure of healthy tissues can lead to severe side effects. We explored the potential of mitochondrial SOD (MnSOD) gene therapy to protect esophageal, pancreatic and bone marrow cells from radiation-induced genomic instability. Specifically, we measured the frequency of homologous recombination (HR) at an integrated transgene in the Fluorescent Yellow Direct Repeat (FYDR) mice, in which an HR event can give rise to a fluorescent signal. Mitochondrial SOD plasmid/liposome complex (MnSOD-PL) was administered to esophageal cells 24 h prior to 29 Gy upper-body irradiation. Single cell suspensions from FYDR, positive control FYDR-REC, and negative control C57BL/6NHsd (wild-type) mouse esophagus, pancreas and bone marrow were evaluated by flow cytometry. Radiation induced a statistically significant increase in HR 7 days after irradiation compared to unirradiated FYDR mice. MnSOD-PL significantly reduced the induction of HR by radiation at day 7 and also reduced the level of HR in the pancreas. Irradiation of the femur and tibial marrow with 8 Gy also induced a significant increase in HR at 7 days. Radioprotection by intraesophageal administration of MnSOD-PL was correlated with a reduced level of radiation-induced HR in esophageal cells. These results demonstrate the efficacy of MnSOD-PL for suppressing radiation-induced HR in vivo.
    Radiation Research 04/2010; 173(4):453-61. · 2.70 Impact Factor