title: Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.
abstract: OBJECTIVE
  To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively.
  
  
  METHODS
  Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined.
  
  
  RESULTS
  MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors.
  
  
  CONCLUSIONS
  MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ashcraft
authors.affiliation: Department of Molecular Biomedical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, North Carolina.
authors.forename: Mary-Keara
authors.initials: MK
authors.lastname: Boss
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Kingshuk
authors.initials: K
authors.lastname: Roy Choudhury
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Fontanella
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Young
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Palmer
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Birer
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Chelsea D
authors.initials: CD
authors.lastname: Landon
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Won
authors.initials: W
authors.lastname: Park
authors.affiliation: Physics and Computing Division, Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Tin
authors.initials: T
authors.lastname: Weitner
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: David M
authors.initials: DM
authors.lastname: Brizel
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina. Electronic address: mark.dewhirst@duke.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D008665:Metalloporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009061:Mouth Mucosa / Q000528:radiation effects*; D058958:Organs at Risk / Q000473:pathology / Q000528:radiation effects; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011897:Random Allocation; D012469:Salivary Glands / Q000473:pathology / Q000528:radiation effects*; D013280:Stomatitis / Q000209:etiology / Q000517:prevention & control; D014987:Xerostomia / Q000209:etiology / Q000517:prevention & control
chemical_list: D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D011837:Radiation-Protective Agents; D011838:Radiation-Sensitizing Agents