Gene Therapy for Mucositis

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

Abstract

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.

Keywords

Radiotherapy Gene therapy Manganese Superoxide Dismutase Antioxidant 

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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

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