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.