Radioprotective effects of the 21-aminosteroid U-74389G for stereotactic radiosurgery.
OBJECTIVE
Future improvements in the results of stereotactic radiosurgery will be related to better patient selection, dose planning, radiosensitization of the target, and, possibly, protection of the brain surrounding the target. 21-Aminosteroids may provide protection against brain radiation injury by inhibition of lipid peroxidation and a selective action on vascular endothelium. We hypothesized that the 21-aminosteroid U-74389G would reduce radiosurgery-related brain injury without attenuating the target volume response.


METHODS
One hundred and forty-five rats were divided into four experimental groups before undergoing radiosurgery: control (n = 47); low-dose U-74389G (5 mg/kg of body weight, n = 30); high-dose U-74389G (15 mg/kg, n = 20); and methylprednisolone (2 mg/kg, n = 48). The drug was administered 1 hour before radiosurgery (4-mm gamma knife collimator) of the normal rat frontal lobe (single-fraction maximum doses of 50, 100, or 150 Gy) was performed. All brains underwent histological examination at 90 or 150 days to evaluate the diameters of necrosis and the findings of radiation-induced vasculopathy, brain edema, and gliosis.


RESULTS
None of the animals that received 50-Gy radiation developed histological changes, whereas all of the animals that received 150-Gy radiation developed radiation necrosis without drug-induced protection from vascular changes or edema. In animals receiving 100-Gy radiation, high-dose aminosteroid reduced radiation-induced vasculopathy at 90 days (P = 0.06) and at 150 days (P = 0.02) and prevented regional edema at 90 days (P = 0.01) and at 150 days (P = 0.03). Low-dose aminosteroid and corticosteroid provided no protection.


CONCLUSIONS
The 21-aminosteroid U-74389G provided protection after a single intravenously administered dose of 15 mg/kg against radiation-induced vasculopathy and edema. High-dose 21-aminosteroids seem to have optimal properties for radiosurgery, surrounding brain protection without reducing the therapeutic effect desired within the target volume.
Kondziolka
D
D
Department of Neurological Surgery, University of Pittsburgh, Pennsylvania, USA.
Somaza
S
S
Martinez
A J
AJ
Jacobsohn
J
J
Maitz
A
A
Lunsford
L D
LD
Flickinger
J C
JC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008775:Methylprednisolone / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology*; D011292:Premedication; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D016634:Radiosurgery; D051381:Rats
D000975:Antioxidants; D011281:Pregnatrienes; D011837:Radiation-Protective Agents; C074965:U 74389F; D008775:Methylprednisolone