Successful cancer radiotherapy is limited by concern for normal tissues, such as the highly sensitive hematopoietic/immune system. The objective of this study was to determine the acute impact of an antioxidant mimetic, MnTE-2-PyP [manganese(III) tetrakis(N-ethyl-2-pyridyl)porphyrin], in modifying radiation induced effects on bone marrow-derived cells. C57BL/6 mice were exposed whole-body to a single fraction of 7 gray (Gy) gamma-rays (60^Co). Subcutaneous (s. c.) injections of MnTE-2-PyP (10 mg/kg) were initiated 1h before and 1, 12 and 24 h post-radiation; and then repeated daily for a maximum of 14 days. Control groups received s.c. injections of saline radiation. On days 4 and 14 post-exposure, subsets were euthanized for analysis of whole blood and spleen DNA synthesis, reactive oxygen species (ROS) production by liver and organ weights. The remaining mice were followed for survival until 46 days post-irradiation. Increased DNA synthesis in samples of whole blood was observed on day 4 with the greatest increase occurring in the animals who received the mimetic 12 and 24 h post radiation. On day 14, the Radiation only group had significantly higher DNA synthesis compared to all other groups. All irradiated groups treated with MnTE-2-PyP were similar to the control on day 14. By day 46, DNA synthesis measured in whole blood had fallen to very low levels, suggesting that reconstitution of the leukocyte fraction was complete. A pattern similar to that in blood was observed for splenocytes. There were no significant differences among groups on day 4 for ROS by liver cells, as measured by the DCFH-DA method. However, by day 14 the Drug + 1h + Radiation and Radiation + 24h + Drug groups had significantly elevated ROS levels compared to the Radiation only group. The results (an earlier burst in DNA synthesis in whole blood and spleen in drug treated animals) suggest that MnTE-2-PyP can modify the timing of hematopoietic reconstitution following whole body irradiation. MnTE-2-PyP had no significant effect on radiation-induced reductions in body mass, relative spleen and thymus masses, and mouse survival.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]