title: A pilot study in rhesus macaques to assess the treatment efficacy of a small molecular weight catalytic metalloporphyrin antioxidant (AEOL 10150) in mitigating radiation-induced lung damage.
abstract: The objective of this pilot study was to explore whether administration of a catalytic antioxidant, AEOL 10150 (C48H56C15MnN12), could reduce radiation-induced lung injury and improve overall survival when administered after 11.5 Gy of whole thorax lung irradiation in a non-human primate model. Thirteen animals were irradiated with a single exposure of 11.5 Gy, prescribed to midplane, and delivered with 6 MV photons at a dose rate of 0.8 Gy min. Beginning at 24 h post irradiation, the AEOL 10150 cohort (n = 7) received daily subcutaneous injections of the catalytic antioxidant at a concentration of 5 mg kg for a total of 4 wk. All animals received medical management, including dexamethasone, based on clinical signs during the planned 180-d in-life phase of the study. All decedent study animals were euthanized for failure to maintain saturation of peripheral oxygen > 88% on room air. Exposure of the whole thorax to 11.5 Gy resulted in radiation-induced lung injury in all animals. AEOL 10150, as administered in this pilot study, demonstrated potential efficacy as a mitigator against fatal radiation-induced lung injury. Treatment with the drug resulted in 28.6% survival following exposure to a radiation dose that proved to be 100% fatal in the control cohort (n = 6). Computed tomography scans demonstrated less quantitative radiographic injury (pneumonitis, fibrosis, effusions) in the AEOL 10150-treated cohort at day 60 post-exposure, and AEOL 10150-treated animals required less dexamethasone support during the in-life phase of the study. Analysis of serial plasma samples suggested that AEOL 10150 treatment led to lower relative transforming growth factor-Beta-1 levels when compared with the control animals. The results of this pilot study demonstrate that treatment with AEOL 10150 results in reduced clinical, radiographic, anatomic, and molecular evidence of radiation-induced lung injury and merits further study as a medical countermeasure against radiation-induced pulmonary injury.
authors.affiliation: *University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore, MD 21201.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Garofalo
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Ward
authors.forename: Ann M
authors.initials: AM
authors.lastname: Farese
authors.forename: Alexander
authors.initials: A
authors.lastname: Bennett
authors.forename: Cheryl
authors.initials: C
authors.lastname: Taylor-Howell
authors.forename: Wanchang
authors.initials: W
authors.lastname: Cui
authors.forename: Allison
authors.initials: A
authors.lastname: Gibbs
authors.forename: Karl L
authors.initials: KL
authors.lastname: Prado
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002384:Catalysis; D003907:Dexamethasone / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D008253:Macaca mulatta; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008970:Molecular Weight; D010100:Oxygen / Q000378:metabolism; D010865:Pilot Projects; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017564:Radiation Pneumonitis / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012119:Respiration / Q000187:drug effects / Q000528:radiation effects; D015996:Survival Rate; D014057:Tomography, X-Ray Computed; D053773:Transforming Growth Factor beta1 / Q000097:blood
chemical_list: C472668:AEOL 10150; D000975:Antioxidants; D008665:Metalloporphyrins; D011837:Radiation-Protective Agents; D053773:Transforming Growth Factor beta1; D003907:Dexamethasone; D010100:Oxygen