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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.
AuthorsDouglas H Weitzel, Artak Tovmasyan, Kathleen A Ashcraft, Alina Boico, Samuel R Birer, Kingshuk Roy Choudhury, James Herndon 2nd, Ramona M Rodriguiz, William C Wetsel, Katherine B Peters, Ivan Spasojevic, Ines Batinic-Haberle, Mark W Dewhirst
JournalEnvironmental and molecular mutagenesis (Environ Mol Mutagen) Vol. 57 Issue 5 Pg. 372-81 (06 2016) ISSN: 1098-2280 [Electronic] United States
PMID27224425 (Publication Type: Journal Article)
Copyright© 2016 Wiley Periodicals, Inc.
Chemical References
  • Antineoplastic Agents
  • Metalloporphyrins
  • Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin
  • Neuroprotective Agents
  • Dacarbazine
  • Cisplatin
  • Temozolomide
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
  • Behavior, Animal (drug effects, radiation effects)
  • Brain (drug effects, metabolism, radiation effects)
  • Brain Neoplasms (drug therapy, radiotherapy)
  • Cell Line, Tumor
  • Cisplatin (administration & dosage, adverse effects, therapeutic use)
  • Combined Modality Therapy
  • Cranial Irradiation
  • Dacarbazine (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
  • Female
  • Humans
  • Metalloporphyrins (administration & dosage, pharmacology, therapeutic use)
  • Mice, Inbred C57BL
  • Mice, Nude
  • Motor Activity (drug effects, radiation effects)
  • Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
  • Oxidation-Reduction
  • Oxidative Stress (drug effects, radiation effects)
  • Temozolomide
  • X-Ray Therapy (adverse effects)

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