Modulation of radiation-induced life shortening by systemic intravenous MnSOD-plasmid liposome gene therapy

Abstract

To determine whether systemic administration of MnSOD-PL protected mice from the acute hematopoietic syndrome and delayed death after total-body irradiation (TBI), C57BL/ 6J mice were injected intravenously with 100 microl liposomes containing 100 microg of human MnSOD-transgene plasmid 24 h prior to irradiation with 9.5 Gy or 1.0 Gy. The dose of 9.5 Gy was lethal to 42% of irradiated control female mice and 74% of irradiated control male mice at 30 days, with bone marrow hypocellularity consistent with the hematopoietic syndrome. A statistically significant increase in survival was observed in MnSOD-PL-treated female mice out to 400 days and in male mice out to 340 days. The incidence of tumors was similar between surviving groups. Between 350 and 600 days, the outcome was similar for both MnSOD-PL-treated and control irradiated groups, consistent with aging, with no difference in gross or microscopic pathological evidence of tumors. Male and female mice receiving 1.0 Gy TBI showed radiation-induced life shortening after 120 days that was decreased by MnSOD-PL administration and that was not associated with an increase in rate of tumor-associated death. Therefore, systemic MnSOD-PL radioprotective gene therapy is not associated with a detectably higher incidence of late carcinogenesis.

Figure 1. Survival from Day 1, by MnSOD-PL Treatment and Radiation Dose Level

C57BL/6J female or male mice were divided into two groups of 150 mice each. One group was injected with MnSOD-PL intravenously. 50 mice from each group were not irradiated. Another 50 mice from each group were administered 1 Gy whole body irradiation with the remaining 50 mice in each group administered 9.5 Gy whole body irradiation 24 hr after injection of MnSOD-PL. The mice were then followed for survival and sacrificed when appearing moribund. The control group was irradiated with no sham injection. Controls were handled exactly as were the injected mice.

Figure 2. Conditional Survival from Day 31, by MnSOD-PL Treatment and Radiation Dose Level

Conditional survival of all mice surviving the first 30 days which was the time of death due to hematopoietic failure was determined on the surviving mice from the six groups from Figure 1. The mice were sacrificed when appearing moribund. The control group was irradiated with no sham injection. Controls were handled exactly as were the injected mice.