Tirilazad does not protect rat brain from brachytherapy-induced injury

Abstract

Acute and chronic brain injury are common sequelae of high-dose focused radiation, as in radiosurgery and brachytherapy. Development of protectors of radiation injury, which would work in brain but not in tumor, would help enhance the therapeutic ratio of focused-radiation therapy. Radiation protection by a clinically available 21-aminosteroid, Tirilazad, was studied in a rat brain brachytherapy model, both in tumor and non-tumor bearing animals. For the tumor model, 9L Glioma/SF line cells were implanted stereotactically into the right frontal lobe of F-344 rats and grew to a sphere of 5.0-mm diameter after 12 days. Animals received a standard brachytherapy dose of 80 Gy to a 5.5-mm radius volume administered by a high-activity removable iodine-125 seed. Radiation damage was evaluated 24 hours after removal of the seeds in all animals and again at 3 months in non-tumor-bearing animals, by T1-weighted gadolinium-enhanced and T2-weighted magnetic resonance imaging (MRI) on a 1.5-T unit. Treated animals received Tirilazad 5 mg/kg intravenously 15 minutes prior to implant, 1 hour after implant, every 6 hours for the duration of the implant, and for 24 hours after removal of the seed. Control animals were administered vehicle only. In both non-tumor-bearing and tumor-bearing rats, no difference in the volume of lesions on enhanced T1 or T2 MRI was seen between the Tirilazad-treated and control groups. In the non-tumor-bearing rats, volume of both T1 enhanced and T2 MRI lesions was significantly reduced at 3 months compared to the values at 24 hours. In the present model, Tirilazad failed to reduce the volume of radiation brain injury from brachytherapy as seen on MRI, studied acutely in tumor-bearing and non-tumor-bearing animals and also at 3 months in non-tumor-bearing rats.