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.

CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+

“…Our previous studies showed MnBuOE to be efficacious in reducing normal tissue injuries and enhancing sensitivity of cancers to radiation and chemotherapies [13], [20], [21], [23], [47], [48]. This study expands the normal tissue benefits of MnBuOE to post-irradiation hippocampal neurogenesis, and provides a strong translational support for the current clinical trial of using MnBuOE as a radioprotector.…”

“…Based on previous pharmacokinetics, toxicology, and efficacy studies [11], [13], [20], [21], [24], [25], a daily dose of 3 mg/kg of each MnP was used. Mice received either two daily subcutaneous (sc) injections (2×1.5 mg/kg) for 7–14 days, or continuous infusion for 2–6 weeks using a model 1004 Alzet® osmotic pump loaded with 28.4 mg/ml MnP.…”

“…The radioprotective effects of MnPs have been demonstrated in several cellular and animal models, and most recently in normal brains, salivary glands, and mouth mucosa [20], [21]. Moreover, in vitro and in vivo studies showed differential effects of MnPs on cancer and normal tissues that implied radio- and chemosensitization of cancer tissues and protection of normal tissues [11], [20], [21], [22], [23], [24].…”

“…Moreover, in vitro and in vivo studies showed differential effects of MnPs on cancer and normal tissues that implied radio- and chemosensitization of cancer tissues and protection of normal tissues [11], [20], [21], [22], [23], [24]. In this study we first examined three MnPs to identify the best drug to be tested for radioprotection of hippocampal neurogenesis.…”

Understanding and targeting dynamic stress responses of the brain: What we have learned and how to improve neurocognitive outcome following neurotoxic insult

“…The importance of the relationship among oxidative stress, disruptions in CNS function and exposure to radiation or specific classes of chemical carcinogens is emphasized in three articles in this special issue [Chmielewski et al, ; Lemon et al, ; Weitzel et al, ]. These articles highlight interventions that can ameliorate the functional decrements caused by radiation and chemotherapy by reducing oxidative stress.…”