Testing Angiotensin Converting Enzyme (ACE) Inhibitors in Combination with EUK 207 for Mitigation of Radiation Pneumonitis
Radiation Research Society
Annual Meeting of the Radiation Research Society
Aim: Because doses of ACE inhibitors required to mitigate radiation pneumonitis are high and may be poorly tolerated by some individuals, we tested the potential of combining low dose ACE inhibitors with antioxidant reagents as mitigators of radiation pneumonitis after total body X-irradiation (TBI). The approach of combinational therapy can also help to understand the mechanism P O S T E R S E S S I O N S 66 Poster Sessions of mitigation. Methods: Rats (WAG/RijCmcr) were exposed to a single dose of 11 Gy TBI followed by a syngeneic bone marrow transplant. Two ACE inhibitors, captopril and enalapril were provided in drinking water starting 7-10 days after irradiation; they were given alone or in combination with the super-oxide dismutase (SOD) catalase mimetic EUK-207. Drug therapy continued for 8 weeks. Rats will be followed up to 120 days. Results: Studies with captopril (100 mg/m2/day) or enalapril (10 mg/m2/day) each combined with EUK-207 (1.8 mg/m2/day) are ongoing. While captopril + EUK-207 shows promise as a mitigating combination when compared to either drug alone, enalapril + EUK-207 does not appear to decrease morbidity, lung structural injury or pulmonary dysfunction. Unlike enalapril, captopril has a reducing -SH moiety which may compliment EUK-207 to diminish oxidative injuries. Conclusions: Captopril but not enalapril, given at low dose in combination with EUK-207, may be effective in mitigating radiation pneumonitis in rats, suggesting a complementary mechanism of -SH and SOD to mitigate oxidative stress. This treatment combination may provide an efficacious alternative to persons experiencing side affects such as severe hypotension with high dose ACE inhibitors alone. This work was funded by RC1 AI 81294 and NIH/NIAID agreements U19-AI-67734. Dosimetry was done by the CMCR Irradiation Core at MCW; histology was done in the Children’s Research Institute at MCW under direction of Dr. Paula North.