Gene Therapy for Mucositis

  • Joel S. Greenberger
  • Michael W. Epperly
  • Peter Wipf
  • Song Li
  • Valerian Kagan
  • Xiang Gao


A major dose limiting toxicity of chemoradiotherapy of head and neck cancer is mucositis. Attempts to decrease radiation damage have included both locally delivered and systemic strategies. A highly effective locally applied radioprotectant is Manganese Superoxide Dismutase-Plasmid Liposomes (MnSOD-PL), which has been shown in animal models with fractionated radiotherapy to the head and neck to be an effective radioprotector, when delivered between each radiotherapy fraction. Intraoral administration of Manganese Superoxide Dismutase-Plasmid Liposomes (MnSOD-PL) prior to single fraction irradiation or immediately before each of multiple fractions of head and neck irradiation significantly reduces oral cavity and oropharyngeal mucositis in the C57BL/6NHsd model. The mechanism is dependent upon mitochondrial targeting of the MnSOD transgene product. A phase I Clinical Trial of administration of MnSOD-PL to patients twice a week during chemoradiotherapy of lung cancer has demonstrated significant protection of the esophagus in patients, who swallow MnSOD-PL. A “mouthwash” administration of MnSOD-PL is being tested in a clinical trial at the University of Pittsburgh Cancer Institute. Reduction of irradiation-induced oral cavity and oropharyngeal mucositis should allow dose escalation in clinical trials of chemoradiotherapy and biological response modifier therapy of head and neck cancers, but more importantly, reduce significant side effects of treatment. An attractive evolution of this gene therapy approach has been the development of small molecule radioprotectants, prominently mitochondrial targeted 4-amino tempo. Mitochondrial targeting has been optimized with the development of hemigramicidin linkers, which deliver concentrated drug to the mitochondria thereby limiting radiation-induced apoptosis. The GS-nitroxide, JP4-039, then delivered in a novel F15 tissue targeted emulsion provides significant radioprotection of normal oral cavity and oropharyngeal mucosa when delivered before single fraction or between fractions of radiotherapy. The ease of administration of oral cavity/oropharynx radioprotectants makes their application in clinical translational protocols both safe and feasible.


Radiotherapy Gene therapy Manganese Superoxide Dismutase Antioxidant 


  1. 1.
    Epperly, MW, Bray JA, Kraeger S, Zwacka R, Engelhardt J, Travis E, Greenberger JS. Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy. Gene Ther. 1998;5:196–208.CrossRefPubMedGoogle Scholar
  2. 2.
    Zwacka RM, Dudus L, Epperly MW, Greenberger JS, Engelhardt JF. Redox gene therapy protects human IB-3 lung epithelial cells against ionizing radiation-induced apoptosis. Human Gene Ther. 1998;9:1381–86.CrossRefGoogle Scholar
  3. 3.
    Epperly MW, Bray JA, Krager S, Berry LA, Gooding W, Engelhardt JF, Zwacka R, Travis EL, Greenberger JS. Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis. Int J Radiat Oncol Phys. 1999;43(1):169–81.Google Scholar
  4. 4.
    Epperly MW, Sikora C, Defilippi S, Bray J, Koe G, Liggitt D, Luketich JD, Greenberger JS. Plasmid/liposome transfer of the human manganese superoxide dismutase (MnSOD) transgene prevents ionizing irradiation-induced apoptosis in human esophagus organ explant culture. Int J Cancer (Radiat Oncol Invest). 2000;90(3):128–37.CrossRefGoogle Scholar
  5. 5.
    Epperly MW, Defilippi S, Sikora C, Gretton J, Kalend K, Greenberger JS. Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation. Gene Ther. 2000;7(12):1011–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Epperly MW, Epstein CJ, Travis EL, Greenberger JS. Decreased pulmonary radiation resistance of manganese superoxide dismutase (MnSOD)-deficient mice is corrected by human manganese Superoxide dismutase-plasmid/liposome (SOD2-PL) intratracheal gene therapy. Radiat Res. 2000;154(4):365–74.Google Scholar
  7. 7.
    Epperly MW, Gretton JA, DeFilippi SJ, Sikora CA, Liggitt D, Koe G, Greenberger JS. Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD-PL) gene therapy. Radiat Res. 2001;155:2–14.CrossRefPubMedGoogle Scholar
  8. 8.
    Epperly MW, Travis EL, Whitsett JA, Epstein CJ, Greenberger JS. Overexpression of manganese superoxide dismutase (MnSOD) in whole lung or alveolar type II (AT-II) cells of MnSOD transgenic mice does not provideintrinsic lung irradiation protection. Radiat Oncol Invest. 2001;96:11–21.Google Scholar
  9. 9.
    Greenberger JS, Kagan VE, Pearce L, Boriseniao G, Tyurina Y, Epperly MW. Modulation of redox signal transduction pathways in the treatment of cancer. Antioxid Redox Signal. 2001;3(3):347–59.CrossRefPubMedGoogle Scholar
  10. 10.
    Epperly MW, Kagan VE, Sikora CA, Gretton JE, Defilippi SJ, Bar-Sagi D, Greenberger JS. Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated irradiation. Int J Cancer (Radiat Oncol Invest). 2001;96(4):221–33.CrossRefGoogle Scholar
  11. 11.
    Epperly MW, Sikora CA, DeFilippi SJ, Gretton JE, Bar-Sagi D, Carlos T, Guo HL, Greenberger JS. Pulmonary irradiation-induced expression of VCAM-1 and ICAM-1 is decreased by MnSOD-PL gene therapy. Biol Blood Bone Marrow Transpl. 2002;8(4)175–87.Google Scholar
  12. 12.
    Epperly MW, Sikora C, Defilippi S, Gretton J, Zhan Q, Kufe DW, Greenberger JS. MnSOD inhibits irradiation-induced apoptosis by stabilization of the mitochondrial membrane against the effects of SAP kinases p38 and Jnk1 translocation. Radiat Res. 2002;157:568–77.CrossRefPubMedGoogle Scholar
  13. 13.
    Kanai AJ, Zeidel ML, Lavelle JP, Greenberger JS, Birder LA, de Groat WC, Apodaca GL, Meyers SA, Ramage R, VanBibber MM, Epperly MW. Manganese superoxide dismutase gene therapy protects against irradiation-induced cystitis. Am J Physiol (Renal Physiol). 2002;44:1152–60.Google Scholar
  14. 14.
    Epperly MW, Defilippi S, Sikora C, Gretton J, Greenberger JS. Radioprotection of lung and esophagus by overexpression of the human manganese superoxide dismutase transgene. Mil Med. 2002;167(1):071.Google Scholar
  15. 15.
    Tarhini AA, Belani C, Luketich JD, Ramalingam SS, Argiris A, Gooding W, Petro D, Kane K, Liggitt D, Championsmith T, Zhang X, Epperly MW, Greenberger JS. A phase I study of concurrent chemotherapy (Paclitaxel and Carboplatin) and thoracic radiotherapy with swallowed manganese superoxide dismutase (MnSOD) plasmid liposome (PL) protection in patients with locally advanced stage III non-small cell lung cancer. Hum Gene Ther. 2011;22(3):336–43.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Fink M, Macias CA, Xiao J, Tyurina YY, Delude RL, Greenberger JS, Kagan VE, Wipf P. Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted antioxidants. Crit Care Med. 2007;35(9):5461–70.CrossRefGoogle Scholar
  17. 17.
    Jiang J, Belikova NA, Xiao J, Zhao Q, Greenberger JS, Wipf P, Kagan VE. A mitochondria-targeted nitroxide/hemi-gramicidin S conjugate protects mouse embryonic cells against g –irradiation. IJROBP. 2008;70(3):816–25.Google Scholar
  18. 18.
    Kagan VE, Bayir A, Bayir H, Stoyanovsky D, Borisenko GG, Tyurina YY, Wipf P, Atkinson J, Greenberger JS, Chapkin RS, Belikova NA. Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: a new strategy in anti-apoptotic drug discovery. Mol Nutr Food Res. 2009;53:104–14.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Jiang J, Stoyanovsky D, Belikova NA, Tyurina YY, Zhao Q, Tungekar MA, Kapralova V, Huang Z, Mintz A, Greenberger JS, Kagan VE. A mitochondria-targeted triphenylphosphonium-conjugated nitroxide functions as a radioprotector/mitigator. Rad Res. 2009;172:706–14.Google Scholar
  20. 20.
    Rajagopalan MS, Gupta K, Epperly MW, Franicola D, Zhang X, Wang H, Zhao H, Tyurin VA, Kagan VE, Wipf P, Kanai A, Greenberger JS. The mitochondria-targeted nitroxide JP4-039 augments potentially lethal irradiation damage repair. In Vivo. 2009;23:717–26.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Belikova NA, Jiang J, Stoyanovsky DA, Greenberger JS, Kagan VE. Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO and protects mouse embryonic cells against irradiation-induced apoptosis. FEBS Lett. 2009;583:1945–50.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Kagan VE, Wipf P, Stoyanovsky D, Greenberger JS, Borisenko G, Belikova NA, Yanamala N, Samhan AAK, Tungekar MA, Jiang J, Tyurina YY, Ji J, Klein-Seetharaman J, Pitt BR, Shvedovah AA, Bayir H. Mitochondrial targeting of electron scavenging antioxidants: regulation of selective oxidation vs random chain reactions. Adv Drug Del Rev. 2009;61(14):1375–85.CrossRefGoogle Scholar
  23. 23.
    Kim H, Bernard ME, Epperly MW, Shen H, Amoscato A, Dixon TM, Doemling AS, Song L, Gao X, Wipf P, Wang H, Zhang X, Kagan VE, Greenberger JS. Amelioration of radiation esophagitis by orally administered p53/mdm2/mdm4 inhibitor (BEB55) or GS-Nitroxide. In Vivo. 2011;25(6):841–9.Google Scholar
  24. 24.
    Nasto L, Seo H, Tilstra J, Robinson A, Clauson C, Sowa G, Ngo K, Dong Q, Lee J, Robbins P, Niedernhofer L, Kang JD, Vo N. Inhibition of NF-kB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Pitt Orthop J. 2013;124:110.Google Scholar
  25. 25.
    Mehanna H, West CML, Nutting C, et al. Head and neck cancer-part 2: treatment and prognostic factors. Br Med J. 2010;41:721–5.Google Scholar
  26. 26.
    Nonzee NJ, Dandade NA, Markossian T, et al. Evaluating the supportive care costs of severe radiochemotherapy-induced mucositis and pharyngitis. Cancer. 2008;113:1446–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Murphy BA, Beaumont JL, Isitt J, et al. Mucositis-related morbidity and resource utilization in head and neck cancer patients receiving radiation therapy with or without chemotherapy. J Pain Symptom Manage. 2009;38:522–32.CrossRefPubMedGoogle Scholar
  28. 28.
    Greenberger JS. Radioprotection. In Vivo. 2009;23:323–36.Google Scholar
  29. 29.
    Epperly MW, Lai SM, Mason N, Lopresi B, Dixon T, Franicola D, Niu Y, Wilson WR, Kanai AJ, Greenberger JS. Effectiveness of combined modality radiotherapy of orthotopic human squamous cell carcinomas in Nu/Nu mice using Cetuximab, Tirapazamine, and MnSOD-plasmid liposome gene therapy. In Vivo. 2010;24:1–8.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Sonis ST. Efficacy of palifermin (keratinocyte growth factor-1) in the amelioration of oral mucositis. Core Evid. 2009;4:199–205.PubMedCentralCrossRefGoogle Scholar
  31. 31.
    Vuyyuri SB, Hamstra DA, Khanna D, et al. Evaluation of D-methionine as a novel oral radiation protector for prevention of mucositis. Clin Cancer Res. 2008;14:2161–70.CrossRefPubMedGoogle Scholar
  32. 32.
    Hamstra DA, Eisbruch A, Naidu MUR, et al. Pharmacokinetic analysis and phase I study of MRX-1024 in patients treated with radiation therapy with or without cisplatinum for head and neck cancer. Clin Cancer Res. 2010;16:2666–76.CrossRefPubMedGoogle Scholar
  33. 33.
    Zheng C, Cotrim AP, Sunshine AN, et al. Prevention of radiation-induced oral mucositis after adenoviral vector-mediated transfer of the keratinocyte growth factor cDNA to mouse submandibular glands. Clin Cancer Res. 2009;15:4641–6.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Mitchell JB, DeGraff W, Kaufman D, et al. Inhibition of oxygen-dependent radiation-induced damage by the nitroxide mimic, tempol. Arch Biochem Biophys. 1991;289:62–70.CrossRefPubMedGoogle Scholar
  35. 35.
    Guo HL, Seixas-Silva JA, Epperly MW, Gretton JE, Shin DM, Greenberger JS. Prevention of irradiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (MnSOD) transgene. Radiat Res. 2003;159:361–70.CrossRefPubMedGoogle Scholar
  36. 36.
    Greenberger JS, Epperly MW. Radioprotective antioxidant gene therapy: potential mechanisms of action. Gene Ther Mol Biol (GTMB). 2004;8:31–44.Google Scholar
  37. 37.
    Greenberger JS, Epperly MW. Pleiotrophic stem cell and tissue effects of ionizing irradiation protection by MnSOD-plasmid liposome gene therapy. In Columbus F, editor. Progress in gene therapy. Nova Science Publications; 2005. pp. 110–8.Google Scholar
  38. 38.
    Epperly MW, Wegner R, Kanai AJ, Kagan V, Greenberger EE, Nie S, Greenberger JS. Irradiated murine oral cavity orthotopic tumor antioxidant pool destabilization by MnSOD-plasmid liposome gene therapy mediates tumor radiosensitization. Radiat Res. 2007;267:289–97.Google Scholar
  39. 39.
    Greenberger JS. Gene therapy approaches for stem cell protection. Gene Ther. 2008;15:100–8.Google Scholar
  40. 40.
    Epperly MW, Gretton JE, Bernarding M, Nie S, Rasul B, Greenberger JS. Mitochondrial localization of copper/zinc superoxide dismutase (Cu/ZnSOD) confers radioprotective functions in vitro and in vivo. Radiat Res. 2003;160:568–78.CrossRefPubMedGoogle Scholar
  41. 41.
    Epperly MW, Goff J, Zhang X, Shields D, Hong WS, Hongmei, Franicola D, Bahnson A, Greenberger EE, Greenberger JS. Increased radioresistance, checkpoint inhibition and impaired migratory capacity of bone marrow stromal cell lines derived from SMAD3−/− mice. Rad Res. 2006;165:671–7.CrossRefGoogle Scholar
  42. 42.
    Hongliang G, Epperly MW, Bernarding M, Nie S, Gretton J, Jefferson M, Greenberger JS. Manganese superoxide dismutase- plasmid/liposome (MnSOD-PL) intratracheal gene therapy reduction of irradiation- induced inflammatory cytokines does not protect orthotopic lewis lung carcinomas. In Vivo. 2003;17:13–22.Google Scholar
  43. 43.
    Epperly MW, Bernarding M, Gretton J, Jefferson M, Nie S, Greenberger JS. Overexpression of the transgene for manganese Superoxide dismutase (MnSOD) in 32D cl 3 cells prevents apoptosis induction by TNF-a, IL-3 withdrawal and ionizing irradiation. Exp Hematol. 2003;31(6):465–74.CrossRefPubMedGoogle Scholar
  44. 44.
    Epperly MW, Osipov AN, Martin I, Kawai K, Borisenko GG, Jefferson M, Bernarding M, Greenberger JS, Kagan VE. Ascorbate as a “redox-sensor” and protector against irradiation-induced oxidative stress in 32D cl 3 hematopoietic cells and subclones overexpressing human manganese Superoxide Dismutase. IJROBP. 2004;58(3):851–61.Google Scholar
  45. 45.
    Kagan VE, Tyurina YY, Bayir H, Chu CT, Kapralov AA, Vlasova II, Belikova NA, Tyurin VA, Amoscato A, Epperly M, Greenberger J, DeKosky S, Shvedova AA, Jiang J. The “pro-apoptotic genies” get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexes. Chem-Biol Interact. 2006;163:15–28.CrossRefPubMedGoogle Scholar
  46. 46.
    Belikova NA, Jiang J, Tyurina YY, Zhao Q, Epperly MW, Greenberger J, Kagan VE. Cardiolipin specific peroxidase reactions of cytochrome c in mitochondria during irradiation induced apoptosis. IJROBP. 2007;69(1):176–85.Google Scholar
  47. 47.
    Tyurin VA, Tyurina YY, Kochanek PM, Hamilton R, DeKosky ST, Greenberger JS, Bayir H, Kagan VE. Oxidative lipidomics of programmed cell death. Methods Enzymol 2008;19(442):375–93.Google Scholar
  48. 48.
    Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA, Jiang J, Stoyanovsky DA, Wipf P, Kochanek P, Greenberger JS, Pitt B, Shvedova AA, Borisenko G. Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med. 2009;46:1439–53.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Epperly MW, Melendez A, Zhang X, Franicola D, Smith T, Greenberger BA, Komanduri P, Greenberger JS. Mitochondrial targeting of a catalase transgene product by plasmid liposomes increases radioresistance in vitro and in vivo. Radiat Res. 2009;171:588–95.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Epperly MW, Chaillet JR, Kalash R, Shaffer B, Goff J, Shields D, Dixon T, Wang H, Berhane H, Kim J-H, Greenberger JS. Conditional radioresistance of tet-inducible manganese superoxide dismutase bone marrow stromal cells. Radiat Res. 2013;180:189–204.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Stoyanovsky DA, Huang Z, Jiang J, Belikova NA, Tyurin V, Epperly MW, Greenberger JS, Bayir H, Kagan VE. A manganese-porphyrin complex decomposes hydrogen peroxide, compartmentalizes into mitochondria, inhibits apoptosis, and acts as a radiation mitigator in vivo. JACS Med Chem Lett. 2011;362:21–34.Google Scholar
  52. 52.
    Atkinson J, Kapralov AA, Yanamala N, Pearce L, Peterson J, Tyurina YY, Epperly MW, Huang Z, Jiang J, Maeda A, Feng W, Wasserloos K, Belikova NA, Tyurin VA, Fletcher J, Wang Y, Vlasova II, Klein-Seetharaman J, Stoyanovsky DA, Bayir H, Pitt BR, Greenberger JS, Kagan VE. A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation induced death. Nature Commun. 2011;2:497.CrossRefGoogle Scholar
  53. 53.
    Berhane H, Epperly MW, Goff J, Kalash R, Cao S, Franicola D, Zhang X, Shields D, Houghton F, Wang H, Sprachman M, Wipf P, Song L, Gao X, D’Andrea A, Guinan E, Parmar K, Greenberger JS. Radiobiologic differences between bone marrow stromal and hematopoietic progenitor cell lines form Fanconi Anemia (FancD2−/−) mice. Radiat Res. in press.Google Scholar
  54. 54.
    Epperly MW, Carpenter M, Agarwal A, Mitra P, Nie S, Greenberger JS. Intra-oral manganese superoxide dismutase plasmid liposome radioprotective gene therapy decreases ionizing irradiation-induced murine mucosal cell cycling and apoptosis. In Vivo. 2004;18:401–10.PubMedGoogle Scholar
  55. 55.
    Epperly MW, Guo HL, Jefferson M, Wong S, Gretton J, Bernarding M, Bar-Sagi D, Greenberger JS. Cell phenotype specific duration of expression of epitope-tagged HA- MnSOD in cells of the murine lung following intratracheal plasmid liposome gene therapy. Gen Ther. 2003;10:163–71.CrossRefGoogle Scholar
  56. 56.
    Guo HL, Wolfe D, Epperly MW, Huang S, Liu K, Glorioso JC, Greenberger J, Blumberg D. Gene transfer of human manganese Superoxide dismutase protects small intestinal villi from radiation injury. J Gastrointest Surg. 2003;7:229–36.CrossRefPubMedGoogle Scholar
  57. 57.
    Carpenter M, Epperly MW, Agarwal A, Nie S, Hricisak L, Niu Y, Greenberger JS. Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes (MnSOD-PL) protects the murine lung from irradiation damage. Gene Therapy. 2005;12:685–90.CrossRefPubMedGoogle Scholar
  58. 58.
    Epperly MW, Zhang X, Nie S, Cao S, Kagan V, Tyurin V, Greenberger JS. MnSOD-Plasmid Liposome gene therapy effects on ionizing irradiation induced lipid peroxidation of the Esophagus. In Vivo. 2005;19:997–1004.PubMedGoogle Scholar
  59. 59.
    Epperly MW, Shen H, Zhang X, Nie S, Cao S, Greenberger JS. Protection of esophageal stem cells from ionizing irradiation by MnSOD-Plasmid Liposome gene therapy. In Vivo. 2005;19:965–74.PubMedGoogle Scholar
  60. 60.
    Epperly MW, Smith T, Wang H, Schlesselman J, Franicola D, Greenberger JS. Modulation of total body irradiation induced life shortening by systemic intravenous MnSOD-plasmid liposome gene therapy. Rad Res. 2008;170(4):437–44.Google Scholar
  61. 61.
    Epperly MW, Wang H, Jones J, Dixon T, Montesinos C, Greenberger JS. Antioxidant-chemoprevention diet ameliorates late effects of total body irradiation and supplements radioprotection by MnSOD-plasmid liposome administration. Radiat Res. 2011;175:759–65.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Greenberger JS, Epperly MW, Gretton J, Jefferson M, Nie S, Bernarding M, Kagan V, Guo HL. Radioprotective gene therapy. Curr Gene Ther. 2003;3:183–95.CrossRefPubMedGoogle Scholar
  63. 63.
    Niu Y, Epperly MW, Shen H, Smith T, Lewis D, Gollin S, Greenberger JS. Intraesophageal MnSOD-Plasmid Liposome administration enhances engraftment and self-renewal capacity of bone marrow derived progenitors of esophageal squamous epithelium. Gene Ther. 2008;15:347–56.CrossRefPubMedGoogle Scholar
  64. 64.
    Niu Y, Wang H, Wiktor-Brown D, Rugo R, Shen H, Huq MS, Engelward B, Epperly M, Greenberger JS. Irradiated esophageal cells are protected from radiation-induced recombination by MnSOD gene therapy. Rad Res. 2010;173:453–61.Google Scholar
  65. 65.
    Rajagopalan MS, Stone, Rwigema J-C, Salimi U, Epperly MW, Goff J, Franicola D, Dixon T, Cao S, Zhang X, Buchholz BM, Bauer AJ, Choi S, Bakkenist C, Wang H, Greenberger JS. Intraesophageal manganese superoxide dismutase-plasmid liposomes ameliorates novel total body and thoracic irradiation sensitivity of homologous deletion recombinant negative nitric oxide synthase-1 (NOS1−/−) mice. Rad Res. 2010;174:297–312.Google Scholar
  66. 66.
    Epperly MW, Bahary N, Quader M, Dewald V, Greenberger JS. The Zebrafish—Danio rerio—is a useful model for measuring the effects of ionizing irradiation. In Vivo. 2012;26(6):889–7.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Jiang J, Kurnikov I, Belikova NA, Xiao J, Zhao Q, Vlasova IL, Amoscato AA, Braslau R, Studer A, Fink MP, Greenberger JS, Wipf P, Kagan VE. Structural requirements for optimized delivery, inhibition of oxidative stress and anti-apoptotic activity of targeted nitroxides. J Pharmacol, Exp Ther. 2007;320(5):1050–60.Google Scholar
  68. 68.
    Fink MP, Macias CA, Xiao J, Tyurina YY, Delude RL, Greenberger JS, Kagan VE, Wipf P. Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted anti-oxidants. Biochem Pharmacol. 2007;74:801–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Hahn SM, Sullivan FJ, DeLuca AM, et al. Evaluation of tempol radioprotection in a murine tumor model. Fred Radic Biol Med. 1997;2:1211–6.CrossRefGoogle Scholar
  70. 70.
    Metz JM, Smith D, Mick R, et al. A phase I study of topical tempol for the prevention of alopecia induced by whole brain radiotherapy. Clin Cancer Res. 2004;10:6411–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Cotrim AP, Yoshikawa M, Sunshine AN, Zheng C, Sowers AL, Zheng C, Sowers AL, Thetford AD, Cook JA, Mitchell JB, Baum BJ. Pharmacological protection from radiation + cisplatin-induced oral mucositis. Int J Radiat Oncol Biol Phys. 2012;83(4):1284–90.Google Scholar
  72. 72.
    Tyurina YY, Tyurin VA, Epperly MW, Greenberger JS, Kagan VE. Oxidative lipidomics of γ-irradiation induced intestinal injury. Free Radic Biol Med. 2008;44:299–314.Google Scholar
  73. 73.
    Frantz M-C, Skoda EM, Davoren J E, Wang Z, Epperly MW, Stripay JL, Tyurin VA, Fink B, Kapralov A, Greenberger JS, Bayir H, Robbins PD, Niedernhofer LJ, Kagan VE, Wipf P. Synthesis and biochemical analysis of mitochondria-targeted nitroxide conjugates based on gramicidin S. JACS (in press).Google Scholar
  74. 74.
    Rwigema J-CM, Beck B, Wang W, Doemling A, Epperly MW, Shields D, Franicola D, Dixon T, Frantz M-C, Wipf P, Tyurina Y, Kagan VE, Wang H, Greenberger JS. Two strategies for the development of mitochondrial-targeted small molecule radiation damage mitigators. Int J Radiat Oncol Biol Phys. 2011;80(3):860–8.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Greenberger JS, Kagan V, Bayir H, Lazo J, Wipf P, Song L, Gao X, Clump D, Epperly MW. Mitochondrial targeted small molecule radiation protectors and radiation mitigators. Front Radiat Oncol. 2012;1(59):1–12.Google Scholar
  76. 76.
    Goff JP, Epperly MW, Shields D, Wipf P, Dixon T, Greenberger JS. Radiobiologic effects of GS-nitroxide (JP4-039) in the hematopoietic syndrome. In Vivo. 2011;25:315–24.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Gao X, Huang Y, Makhov AM, Epperly M, Lu J, Grab S, Zhang P, Rohan L, Xie XQ, Wipf P, Greenberger J, Li S. Nanoassembly of surfactants with interfacial drug-interactive motifs as tailor-designed drug carriers. Mol Pharm. 2013 Jan 7;10(1):187–98. doi: 10.1021/mp300319m. Epub 2012 Dec 1.Google Scholar
  78. 78.
    Ji J, Kline AE, Amoscato A, Samhan-Arias AK, Sparvero LJ, Tyurin VA, Tyurina YY, Fink B, Manole MD, Puccio AM, Okonkwo DO, Cheng JP, Alexander H, Clark RS, Kochanek PM, Wipf P, Kagan VE, Bayir H. Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. Nature Neuroscience. 2012 Oct;15(10):1407–13.Google Scholar
  79. 79.
    Cotrim AP, Sowers AL, Lodde BM, et al. Kinetics of tempol for prevention of xerostomia following head and neck irradiation in a mouse model. Clin Cancer Res. 2005;11:7564–8.CrossRefPubMedGoogle Scholar
  80. 80.
    Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590–8.Google Scholar
  81. 81.
    Buentzel J, Micke O, Adamietz IA, et al. Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study. Int J Radiat Oncol Biol Phys. 2006;64:684–91.CrossRefPubMedGoogle Scholar
  82. 82.
    Berhane H, Kalash R, Epperly MW, Goff J, Xu K, Franicola D, Zhang X, Dixon T, Shields D, Wang H, Wipf P, Song L, Gao X, Greenberger JS. Amelioration of irradiation induced oral cavity mucositis and distant bone marrow suppression in Fancd2−/− (FVB/N) mice by intraoral JP4-039/F15. Radiat Res. (submitted).Google Scholar
  83. 83.
    Berhane H, Goff J, Epperly MW, Xu K, Franicola D, Zhang X, Dixon T, Shields D, Wang H, Wipf P, Parmar K, Ferris R, Greenberger JS. Intraoral GS-Nitroxide JP4-039 protects oral mucosa of Fancd2−/− (C57BL/6) mice during irradiation of orthotopic tumors. Cancer Res. (submitted).Google Scholar
  84. 84.
    Epperly MW, Guo HL, Bernarding M, Gretton J, Jefferson M, Greenberger JS. Delayed intratracheal injection of manganese superoxide dismutase (MnSOD)-plasmid/liposomes provides suboptimal protection against irradiation-induced pulmonary injury compared to treatment before irradiation. Gene Ther Mol Biol. 2003;7:61–8.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Joel S. Greenberger
    • 1
  • Michael W. Epperly
    • 1
  • Peter Wipf
    • 2
  • Song Li
    • 3
  • Valerian Kagan
    • 4
  • Xiang Gao
    • 3
  1. 1.Department of Radiation OncologyUniversity of Pittsburgh Medical CenterPittsburghUSA
  2. 2.Department of Chemistry and Center for Chemical Methodologies and Library DevelopmentUniversity of PittsburghPittsburghUSA
  3. 3.Department of Pharmaceutical ScienceUniversity of PittsburghPittsburghUSA
  4. 4.Department of Environmental and Occupational Health, School of Public HealthUniversity of PittsburghPittsburghUSA

Personalised recommendations