title: Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier.
abstract: Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP(5+) (Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2-PyP(5+) after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP(5+) accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP(5+) completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP(5+) treatment rescued the negative effects of both temozolomide ± RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2-PyP(5+) did not negatively affect rotorod performance. Additionally, MnTnBuOE-2-PyP(5+) sensitized glioblastomas to either RT ± temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP(5+) and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP(5+) may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372-381, 2016. © 2016 Wiley Periodicals, Inc.
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: Alina
authors.initials: A
authors.lastname: Boico
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 Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kingshuk
authors.initials: K
authors.lastname: Roy Choudhury
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
authors.forename: James
authors.initials: J
authors.lastname: Herndon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.|Department of Mouse Behavioral and Neuroendocrine Analysis Core Facility, 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 Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina.|Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.|Department of Neurobiology, 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: 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.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects* / Q000528:radiation effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009043:Motor Activity / Q000187:drug effects / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D000077204:Temozolomide; D014964:X-Ray Therapy / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D018696:Neuroprotective Agents; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide
keywords: brain; oxidative stress; porphyrin; radiation mitigation