Title

Radioprotection of the brain white matter by Mn(III) n-Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+

Authors

Douglas H. Weitzel, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Artak Tovmasyan, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Kathleen A. Ashcraft, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Zrinka Rajic, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Tin Weitner, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Chunlei Liu, Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina.
Wei Li, Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina.
Anne F. Buckley, 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.
Mark R. Prasad, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Kenneth H. Young, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Ramona M. Rodriguiz, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
William C. Wetsel, 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.
Katherine B. Peters, Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Ivan Spasojevic, PK/PD BioAnalytical DCI Shared Resource, Duke University Medical Center, Durham, North Carolina.
James E. Herndon, Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
Ines Batinic-Haberle, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Mark W. Dewhirst, 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.

Document Type

Article

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.

Medical Subject Headings

Animals; Brain Neoplasms (drug therapy, pathology, radiotherapy); Cell Line, Tumor; Corpus Callosum (radiation effects); Glioblastoma (drug therapy, pathology, radiotherapy); Humans; Metalloporphyrins (administration & dosage, pharmacology); Mice; Mice, Inbred C57BL; Motor Activity (drug effects, radiation effects); Oxidative Stress (drug effects); Radiation-Protective Agents (administration & dosage, pharmacology); White Matter (pathology, radiation effects)

Publication Date

1-1-2015

Publication Title

Molecular cancer therapeutics

E-ISSN

1538-8514

Volume

14

Issue

1

First Page

70

Last Page

9

PubMed ID

25319393

Digital Object Identifier (DOI)

10.1158/1535-7163.MCT-14-0343

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