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Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n ‐butoxyethylpyridylporphyrin‐based redox modifier
Author(s) -
Weitzel Douglas H.,
Tovmasyan Artak,
Ashcraft Kathleen A.,
Boico Alina,
Birer Samuel R.,
Roy Choudhury Kingshuk,
Herndon James,
Rodriguiz Ramona M.,
Wetsel William C.,
Peters Katherine B.,
Spasojevic Ivan,
BatinicHaberle Ines,
Dewhirst Mark W.
Publication year - 2016
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.22021
Subject(s) - temozolomide , radiation therapy , cisplatin , neurotoxicity , brain tumor , chemotherapy , white matter , medicine , oxidative stress , cancer research , chemistry , toxicity , pathology , magnetic resonance imaging , radiology
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.