title: Radioprotection of the brain white matter by Mn(III) n-Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+.
abstract: Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP(5+)(Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP(5+) before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP(5+)/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP(5+)/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP(5+)/RT. Our data demonstrate that MnTnBuOE-2-PyP(5+) is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP(5+) combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP(5+) with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP(5+) has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Weitzel
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 Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ashcraft
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Rajic
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Tin
authors.initials: T
authors.lastname: Weitner
authors.affiliation: Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina. Animal Pathology Core, Duke University Medical Center, Durham, North Carolina.
authors.forename: Anne F
authors.initials: AF
authors.lastname: Buckley
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Prasad
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 Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina. Department of Neurobiology and Cell Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Peters
authors.affiliation: PK/PD BioAnalytical DCI Shared Resource, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
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. Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina. dewhirst@radonc.duke.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003337:Corpus Callosum / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000528:radiation effects*; D018384:Oxidative Stress / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D066127:White Matter / Q000473:pathology / Q000528:radiation effects*
chemical_list: D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D011837:Radiation-Protective Agents