title: AEOL 10150 Mitigates Radiation-Induced Lung Injury in the Nonhuman Primate: Morbidity and Mortality are Administration Schedule-Dependent.
abstract: Pneumonitis and fibrosis are potentially lethal, delayed effects of acute radiation exposure. In this study, male rhesus macaques received whole-thorax lung irradiation (WTLI) with a target dose of 10.74 Gy prescribed to midplane at a dose rate of 0.80 ± 0.05 Gy/min using 6 MV linear accelerator-derived photons. The study design was comprised of four animal cohorts: one control and three treated with AEOL 10150 (n = 20 animals per cohort). AEOL 10150, a metalloporphyrin antioxidant, superoxide dismutase mimetic was administered by daily subcutaneous injection at 5 mg/kg in each of three schedules, beginning 24 ± 2 h postirradiation: from day 1 to day 28, day 1 to day 60 or a divided regimen from day 1 to day 28 plus day 60 to day 88. Control animals received 0.9% saline injections from day 1 to day 28. All animals received medical management and were followed for 180 days. Computed tomography (CT) scan and baseline hematology values were assessed prior to WTLI. Postirradiation monthly CT scans were collected, and images were analyzed for evidence of lung injury (pneumonitis, fibrosis, pleural and pericardial effusion) based on differences in radiodensity characteristics of the normal versus damaged lung. The primary end point was survival to 180 days based on all-cause mortality. The latency, incidence and severity of lung injury were assessed through clinical, radiographic and histological parameters. A clear survival relationship was observed with the AEOL 10150 treatment schedule and time after lethal WTLI. The day 1-60 administration schedule increased survival from 25 to 50%, mean survival time of decedents and the latency to nonsedated respiratory rate to >60 or >80 breaths/min and diminished quantitative radiographic lung injury as determined by CT scans. It did not affect incidence or severity of pneumonitis/fibrosis as determined by histological evaluation, pleural effusion or pericardial effusion as determined by CT scans. Analysis of the Kaplan-Meier survival curves suggested that treatment efficacy could be increased by extending the treatment schedule to 90 days or longer after WTLI. No survival improvement was noted in the AEOL 10150 cohorts treated from day 1-28 or using the divided schedule of day 1-28 plus day 60-88. These results suggest that AEOL 10150 may be an effective medical countermeasure against severe and lethal radiation-induced lung injury.
authors.affiliation: a   Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
authors.affiliation: a   Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland.
authors.forename: Allison
authors.initials: A
authors.lastname: Gibbs
authors.affiliation: a   Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Farese
authors.affiliation: b   SNBL USA Ltd., Everett, Washington.
authors.forename: Kory
authors.initials: K
authors.lastname: Barrow
authors.affiliation: a   Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bennett
authors.affiliation: c   Clinical Research Management, Frederick, Maryland.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Taylor-Howell
authors.affiliation: d   VA Maryland Health Care System, Baltimore, Maryland.
authors.forename: Abdul
authors.initials: A
authors.lastname: Kazi
authors.affiliation: a   Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland.
authors.forename: Karl
authors.initials: K
authors.lastname: Prado
authors.affiliation: e   Charles River Laboratories, Durham, North Carolina.
authors.forename: George
authors.initials: G
authors.lastname: Parker
authors.affiliation: f Statistician, Rockville, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Jackson
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D053208:Kaplan-Meier Estimate; D055370:Lung Injury / Q000188:drug therapy* / Q000401:mortality*; D008253:Macaca mulatta; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D009017:Morbidity; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000401:mortality*; D013997:Time Factors
chemical_list: C472668:AEOL 10150; D008665:Metalloporphyrins